Patent Publication Number: US-2020276100-A1

Title: Photoprotective compositions containing malassezia-derived compounds and/or chemical analogs thereof

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     The present invention claims benefit to U.S. provisional application No. 62/742,657, filed Oct. 8, 2018. The entire contents of the aforementioned application are incorporated by reference. Additionally, the entire contents of U.S. provisional application No. 62/306,468, filed Mar. 10, 2016, U.S. provisional application No. 62/656,769, filed Apr. 12, 2018, U.S. provisional application No. 62/668,007, filed May 7, 2018, U.S. provisional application No. 62/685,800, filed Jun. 15, 2018, U.S. provisional application No. 62/686,912, filed Jun. 19, 2018, U.S. provisional application No. 62/722,412, filed Aug. 24, 2018, U.S. patent application Ser. No. 15/455,932, filed Mar. 10, 2017, now U.S. Pat. No. 10,131,631, U.S. patent application Ser. No. 16/382,891, filed Apr. 12, 2019, U.S. patent application Ser. No. 16/405,127, filed May 7, 2019, and U.S. patent application Ser. No. 16/441,522, filed Jun. 14, 2019 are hereby incorporated herein by reference. 
    
    
     FIELD OF INVENTION 
     The present invention relates to compounds and compositions having, among other beneficial properties, photoprotective properties. Compounds and compositions of the present invention generally involve  Malassezia -derived compounds and/or chemical analogs thereof. The compounds and compositions of the present invention Methods of using the compounds and compositions of the present invention are also contemplated. 
     BACKGROUND OF THE INVENTION 
     Individuals around the world use skin brightening agents to achieve a number of cosmetic goals, including producing an anti-aging effect, correcting sun damage, and meeting certain cultural standards of beauty. Many commercially available skin brightening products, while effective to varying degrees, contain harmful ingredients, some of which have been linked to cancer. Thus, there exists a need for novel skin brightening agents and formulations that exhibit higher levels of safety and/or efficacy than agents currently on the market. 
       Malassezia  is a genus of lipophilic yeast commonly found in the normal flora of human skin.  Malassezia  is responsible for a number of skin diseases, including tinea versicolor (pityriasis versicolor), seborrheic dermatitis, and atopic dermatitis. 
     The natural habitat for  M. furfur  is the upper epidermis. However, exposure to ultraviolet light destroys the organism in its natural habitat. Therefore, UV filtering agents may be necessary for the survival of the organism. Two such UV-filtering indoles produced by the organism have been identified: pityriacitrin and pityrialactone. Pityriacitrin, first described in Mayser et al., 2002, is synthesized by  M. furfur . It is a stable yellow lipophilic compound showing broad absorption in the UVA, UVB, and UVC spectrum. A similar compound from the genus  Paracoccus  has been isolated as a UV protective agent. (Zhang et al., 2018; US 2006/0067897). 
     Gambichler et al., 2007 investigated the UV protective effect of pityriacitrin in humans using in vitro and in vivo test methods. Spectrophotometry of pityriacitrin cream and vehicle was performed in the 290-400 nm wavelength range. UV transmission and the sun protection factor (“SPF”) were assessed for different cream formulations. Using colorimetry, the authors evaluated erythema and pigmentation following irradiation of cream-protected and non-protected skin of healthy subjects. UVB as well as UVA transmission decreased with increasing pityriacitrin concentrations. An increase of pityriacitrin concentration of 1.25, 2.5, and 5% was associated with slightly increasing SPFs of 1.4, 1.5, and 1.7, respectively. The in vivo tests confirmed the validity of the SPF of pityriacitrin 5% cream determined in vitro. Overall, the UV protective effect of pityriacitrin was very weak, suggesting that pityriacitrin likely is only an inferior cofactor in the development of hypopigmentation in pityriasis versicolor alba lesions following sun exposure. 
     Further studies of the UV filtering effects of pityriacitrin were performed on human skin microflora. (Machowinski et al., 2006). The authors determined pityriacitrin has a UV-protective effect on  Candida albicans  and staphylococci with no toxicity in the ranges tested. The UV protective properties of pityrialactone have also been confirmed in a yeast model. (Mayser et al., 2003). Pityrialactone appears to be responsible for the yellow fluorescence of Tinea Versicolor under Wood&#39;s Light examination. 
     Tinea versicolor is a non-contagious skin disease caused by  Malassezia  overgrowth that locally alters pigmentation levels.  Malassezia  yeasts have two metabolic pathways for synthesizing melanin and tryptophan-derived indole pigments. Malassezin and Indirubin are tryptophan metabolites of  Malassezia  that may contribute to the depigmentation characteristic of  Malassezia  overgrowth. 
     The invention disclosed herein utilizes compounds produced by or derived from  Malassezia  yeast, including Malassezin, Indirubin, and chemical analogs thereof, as the basis for safe and efficacious skin brightening and skin darkening compositions. Photoprotective compositions comprising Malassezin, Indirubin, and chemical analogs thereof are also disclosed herein. 
     SUMMARY OF THE INVENTION 
     One embodiment of the present invention is a compound for brightening skin. The compound has a structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     Another embodiment of the present invention is a compound for inducing melanocyte apoptosis. The compound has a structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     An additional embodiment of the present invention is a compound for modulating arylhydrocarbon receptor (AhR) activity. The compound has a structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     A further embodiment of the present invention is a compound for modulating melanogenesis. The compound has a structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     Another embodiment of the present invention is a compound for modulating melanin concentration. The compound has a structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     An additional embodiment of the present invention is a composition comprising a compound. The compound has a structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     A further embodiment of the present invention is a method for brightening skin in a subject. The method comprises contacting the subject with a compound, the compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     Another embodiment of the present invention is a method for inducing melanocyte apoptosis in a subject. The method comprises contacting the subject with a compound, the compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     An additional embodiment of the present invention is a method for modulating arylhydrocarbon receptor (AhR) activity in a subject. The method comprises contacting the subject with a compound, the compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     A further embodiment of the present invention is a method for modulating melanogenesis in a subject. The method comprises contacting the subject with a compound, the compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     Another embodiment of the present invention is a method for modulating melanin concentration in a subject. The method comprises contacting the subject with a compound, the compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     An additional embodiment of the present invention is a composition. The composition comprises one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     A further embodiment of the present invention is a method for brightening skin in a subject. The method comprises contacting the subject with one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     Another embodiment of the present invention is a method for inducing melanocyte apoptosis in a subject. The method comprises contacting the subject with one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     An additional embodiment of the present invention is a method for modulating arylhydrocarbon receptor (AhR) activity in a subject. The method comprises contacting the subject with one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     A further embodiment of the present invention is a method for modulating melanogenesis in a subject. The method comprises contacting the subject with one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     Another embodiment of the present invention is a method for modulating melanin concentration in a subject. The method comprises contacting the subject with one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     An additional embodiment of the present invention is a composition. The composition comprises one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     A further embodiment of the present invention is a composition for brightening skin. The composition comprises one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     Another embodiment of the present invention is a composition for inducing melanocyte apoptosis. The composition comprises one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     An additional embodiment of the present invention is a composition for modulating arylhydrocarbon receptor (AhR) activity. The composition comprises one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     A further embodiment of the present invention is a composition for modulating melanogenesis. The composition comprises one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     Another embodiment of the present invention is a composition for modulating melanin concentration. The composition comprises one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     An additional embodiment of the present invention is a method for brightening skin in a subject. The method comprises contacting the subject with a composition, the composition comprising one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     A further embodiment of the present invention is a method for inducing melanocyte apoptosis in a subject. The method comprises contacting the subject with a composition, the composition comprising one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     Another embodiment of the present invention is a method for modulating arylhydrocarbon receptor (AhR) activity in a subject. The method comprises contacting the subject with a composition, the composition comprising one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     An additional embodiment of the present invention is a method for modulating melanogenesis in a subject. The method comprises contacting the subject with a composition, the composition comprising one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     A further embodiment of the present invention is a method for modulating melanin concentration in a subject. The method comprises contacting the subject with a composition, the composition comprising one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     Another embodiment of the present invention is a composition. The composition comprises a  Malassezia  yeast and a cosmetically or pharmaceutically acceptable vehicle, diluent, or carrier. 
     An additional embodiment of the present invention is a composition. The composition comprises a compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     wherein:
 
X is selected from the group consisting of NR 14  and O; Y is a covalent bond, CR 5 R 6 , O, or NR 15 ; R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , R 10 , and R 11  are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R 16 , or OR 16 ; R 13 , R 14 , and R 15  are independently hydrogen or R 16 ; R 5  and R 6  are independently selected from the group consisting of hydrogen, hydroxyl, OR 16 , R 16 , and C 3-6  cycloalkyl, or R 5  and R 6  combine to form an oxo (═O) group or a C 3-6  cycloalkyl; R 12  is selected from the group consisting of hydrogen, —COR a , and R 16 ; each R 16  is independently C 1-9  alkyl, C 2-9  alkenyl, or C 2-9  alkynyl; and, R a  is selected from the group consisting of hydrogen, hydroxyl, and OR 16 ; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof, and a cosmetically or pharmaceutically acceptable vehicle, diluent, or carrier.
 
     A further embodiment of the present invention is a composition. The composition comprises a compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     wherein:
 
R 1 , R 4 , R 5 , R 6 , R 9 , and R 10  are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13  and —CHO; R 2  and R 3  are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13  and —CHO, or R 2  and R 3  combine to form a 5- or 6-membered heterocyclyl; R 7  and R 8  are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13  and —CHO, or R 7  and R 8  combine to form a 5- or 6-membered heterocyclyl; R 11  and R 12  are independently hydrogen or R 13 ; and, each R 13  is independently C 1-9  alkyl, C 2-9  alkenyl, or C 2-9  alkynyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof, and a cosmetically or pharmaceutically acceptable vehicle, diluent, or carrier.
 
     Another embodiment of the present invention is a composition. The composition comprises a compound listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof, and a cosmetically or pharmaceutically acceptable vehicle, diluent, or carrier. 
     An additional embodiment of the present invention is a method of treating or preventing UV-induced skin damage in a subject. The method comprises contacting the subject with any of the compositions disclosed herein. 
     A further embodiment of the present invention is a method of treating or preventing UV-induced erythema in a subject. The method comprises contacting the subject with any of the compositions disclosed herein. 
     Another embodiment of the present invention is a method of treating or preventing UV-induced aging of the skin in a subject. The method comprises contacting the subject with any of the compositions disclosed herein. 
     An additional embodiment of the present invention is a method of treating or preventing sunburn in a subject. The method comprises contacting the subject with any of the compositions disclosed herein. 
     A further embodiment of the present invention is a method of treating or preventing UV-induced hyperpigmentation in a subject. The method comprises contacting the subject with any of the compositions disclosed herein. 
     Another embodiment of the present invention is a method for brightening skin in a subject. The method comprises contacting the subject with any of the compositions disclosed herein. 
     An additional embodiment of the present invention is a method for inducing melanocyte apoptosis in a subject. The method comprises contacting the subject with any of the compositions disclosed herein. 
     A further embodiment of the present invention is a method for modulating arylhydrocarbon receptor (AhR) activity in a subject. The method comprises contacting the subject with any of the compositions disclosed herein. 
     Another embodiment of the present invention is a method for modulating melanogenesis in a subject. The method comprises contacting the subject with any of the compositions disclosed herein. 
     An additional embodiment of the present invention is a method for modulating melanin concentration in a subject. The method comprises contacting the subject with any of the compositions disclosed herein. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawings will be provided by the Office upon request and payment of the necessary fee. 
         FIGS. 1-2  are tables showing mean tissue viability and melanin concentration data ascertained from separate experiments with MelanoDerm™ substrates treated with varying concentrations of the test articles shown. 
         FIG. 3  shows compounds produced by  Malassezia.    
         FIGS. 4-5  are tables showing mean tissue viability and melanin concentration data ascertained from separate experiments with MelanoDerm™ substrates treated with varying concentrations of the test articles/test compositions shown. 
         FIGS. 6A-6B  show synthesis schemes for AB17590 ( FIG. 6A ) and AB17653, AB17654, AB17655, AB17656, AB17657, and AB17658 ( FIG. 6B ). 
         FIG. 7  is a schematic showing a skin treatment template for Skin Type IV patients. Values indicate UV dose for a given area in mJ/cm 2 . 
         FIG. 8  is a table showing a Dualight scale for Skin Types I-VI. 
         FIG. 9  is a table showing Mexameter MX 16 measurements of melanin and erythema at Day 8 after Day 7 irradiation. 
         FIG. 10  is a table showing Mexameter MX 16 measurements of melanin and erythema at Day 15 after Day 14 irradiation. 
         FIG. 11  is a table showing an erythema scale of numerical values associated with various degrees of erythema. 
         FIG. 12  is a photograph showing a subject&#39;s skin 24 hours after irradiation with various levels of UV according to the skin treatment template shown in  FIG. 7 . The minimal erythema dose (“MED”) was 120 mJ UVB 24 hours after irradiation. 
         FIG. 13  is a photograph showing test sites on a subject&#39;s skin at Day 7. 
         FIG. 14  is a photograph showing test sites on a subject&#39;s skin at Day 8, 24 hours post-irradiation with 120 mJ UVB. 
         FIG. 15  is a photograph showing test sites on a subject&#39;s skin at Day 14 after an additional week of Malassezin therapy. Treatment areas were dosed with 120 mJ UVB. 
         FIG. 16  is a photograph showing test sites on a subject&#39;s skin at Day 15, 24 hours post-irradiation with 120 mJ UVB. Note erythema at vehicle site for Days 7 and 9. Also note minimal to mild erythema at Malassezin 1%-treated sites for Day 14, 10, and 8, with trace erythema at Days 1 and 3. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     One embodiment of the present invention is a compound for brightening skin. The compound has a structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     Another embodiment of the present invention is a compound for inducing melanocyte apoptosis. The compound has a structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     An additional embodiment of the present invention is a compound for modulating arylhydrocarbon receptor (AhR) activity. The compound has a structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     A further embodiment of the present invention is a compound for modulating melanogenesis. The compound has a structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     Another embodiment of the present invention is a compound for modulating melanin concentration. The compound has a structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     An additional embodiment of the present invention is a composition comprising a compound. The compound has a structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     A further embodiment of the present invention is a method for brightening skin in a subject. The method comprises contacting the subject with a compound, the compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     Another embodiment of the present invention is a method for inducing melanocyte apoptosis in a subject. The method comprises contacting the subject with a compound, the compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     An additional embodiment of the present invention is a method for modulating arylhydrocarbon receptor (AhR) activity in a subject. The method comprises contacting the subject with a compound, the compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     A further embodiment of the present invention is a method for modulating melanogenesis in a subject. The method comprises contacting the subject with a compound, the compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     Another embodiment of the present invention is a method for modulating melanin concentration in a subject. The method comprises contacting the subject with a compound, the compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     An additional embodiment of the present invention is a composition. The composition comprises one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     In one aspect of this embodiment, the composition comprises a first compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof; and, a second compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     A further embodiment of the present invention is a method for brightening skin in a subject. The method comprises contacting the subject with one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     In one aspect of this embodiment, the subject is contacted with a first compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof; and, a second compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     Another embodiment of the present invention is a method for inducing melanocyte apoptosis in a subject. The method comprises contacting the subject with one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     In one aspect of this embodiment, the subject is contacted with a first compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof; and, a second compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     An additional embodiment of the present invention is a method for modulating arylhydrocarbon receptor (AhR) activity in a subject. The method comprises contacting the subject with one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     In one aspect of this embodiment, the subject is contacted with a first compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof; and, a second compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     A further embodiment of the present invention is a method for modulating melanogenesis in a subject. The method comprises contacting the subject with one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     In one aspect of this embodiment, the subject is contacted with a first compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof; and, a second compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     Another embodiment of the present invention is a method for modulating melanin concentration in a subject. The method comprises contacting the subject with one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     In one aspect of this embodiment, the subject is contacted with a first compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof; and, a second compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     An additional embodiment of the present invention is a composition. The composition comprises one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     A further embodiment of the present invention is a composition for brightening skin. The composition comprises one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     Another embodiment of the present invention is a composition for inducing melanocyte apoptosis. The composition comprises one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     An additional embodiment of the present invention is a composition for modulating arylhydrocarbon receptor (AhR) activity. The composition comprises one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     A further embodiment of the present invention is a composition for modulating melanogenesis. The composition comprises one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     Another embodiment of the present invention is a composition for modulating melanin concentration. The composition comprises one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     An additional embodiment of the present invention is a method for brightening skin in a subject. The method comprises contacting the subject with a composition, the composition comprising one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     A further embodiment of the present invention is a method for inducing melanocyte apoptosis in a subject. The method comprises contacting the subject with a composition, the composition comprising one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     Another embodiment of the present invention is a method for modulating arylhydrocarbon receptor (AhR) activity in a subject. The method comprises contacting the subject with a composition, the composition comprising one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     An additional embodiment of the present invention is a method for modulating melanogenesis in a subject. The method comprises contacting the subject with a composition, the composition comprising one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     A further embodiment of the present invention is a method for modulating melanin concentration in a subject. The method comprises contacting the subject with a composition, the composition comprising one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     In preferred embodiments, the compositions of the present invention comprise the compounds listed in Table 3. 
     In other preferred embodiments, the compositions of the present invention comprise the compounds listed in Table 4. 
     In additional preferred embodiments, the compositions of the present invention comprise the compounds listed in Table 5. 
     In further preferred embodiments, the compositions of the present invention comprise the compounds listed in Table 6. 
     In other preferred embodiments, the compositions of the present invention comprise the compounds listed in Table 7. 
     In additional preferred embodiments, the methods of the present invention comprise contacting a subject with a composition comprising the compounds listed in Table 3. 
     In further preferred embodiments, the methods of the present invention comprise contacting a subject with a composition comprising the compounds listed in Table 4. 
     In other preferred embodiments, the methods of the present invention comprise contacting a subject with a composition comprising the compounds listed in Table 5. 
     In additional preferred embodiments, the methods of the present invention comprise contacting a subject with a composition comprising the compounds listed in Table 6. 
     In further preferred embodiments, the methods of the present invention comprise contacting a subject with a composition comprising the compounds listed in Table 7. 
     Another embodiment of the present invention is a composition. The composition comprises a  Malassezia  yeast, and a cosmetically or pharmaceutically acceptable vehicle, diluent, or carrier. 
     An additional embodiment of the present invention is a composition. The composition comprises a compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     wherein:
 
X is selected from the group consisting of NR 4  and O; Y is a covalent bond, CR 5 R 6 , O, or NR 15 ; R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , R 10 , and R 11  are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R 16 , or OR 16 ; R 13 , R 14 , and R 15  are independently hydrogen or R 16 ; R 5  and R 6  are independently selected from the group consisting of hydrogen, hydroxyl, OR 16 , R 16 , and C 3-6  cycloalkyl, or R 5  and R 6  combine to form an oxo (═O) group or a C 3-6  cycloalkyl; R 12  is selected from the group consisting of hydrogen, —COR a , and R 16 ; each R 16  is independently C 1-9  alkyl, C 2-9  alkenyl, or C 2-9  alkynyl; and, R a  is selected from the group consisting of hydrogen, hydroxyl, and OR 16 ; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof, and a cosmetically or pharmaceutically acceptable vehicle, diluent, or carrier.
 
     A further embodiment of the present invention is a composition. The composition comprises a compound having the structure of the following formula: 
     
       
         
         
             
             
         
       
     
     wherein:
 
R 1 , R 4 , R 5 , R 6 , R 9 , and R 10  are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13  and —CHO; R 2  and R 3  are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13  and —CHO, or R 2  and R 3  combine to form a 5- or 6-membered heterocyclyl; R 7  and R 5  are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13  and —CHO, or R 7  and R 8  combine to form a 5- or 6-membered heterocyclyl; R and R 12  are independently hydrogen or R 13 ; and, each R 13  is independently C 1-9  alkyl, C 2-9  alkenyl, or C 2-9  alkynyl; or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof, and a cosmetically or pharmaceutically acceptable vehicle, diluent, or carrier.
 
     Another embodiment of the present invention is a composition. The composition comprises a compound listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof, and a cosmetically or pharmaceutically acceptable vehicle, diluent, or carrier. 
     In preferred embodiments, any of the compositions of the present invention prevent UV-induced erythema in a subject. 
     In preferred embodiments, any of the compositions of the present invention reduce epidermal melanin in a subject. 
     In preferred embodiments, any of the compositions of the present invention produce a photo-protective or UV-protective effect in a subject. 
     In preferred embodiments, any of the compositions of the present invention filter, absorb, or reflect UV. 
     In preferred embodiments, any of the compositions of the present invention prevent hyperpigmentation and/or promote hypopigmentation. 
     In preferred embodiments, any of the compositions of the present invention is a sunscreening agent, a photo-protective agent, and/or a UV-protective agent. 
     An additional embodiment of the present invention is a method of treating or preventing UV-induced skin damage in a subject. The method comprises contacting the subject with any of the compositions disclosed herein. 
     A further embodiment of the present invention is a method of treating or preventing UV-induced erythema in a subject. The method comprises contacting the subject with any of the compositions disclosed herein. 
     Another embodiment of the present invention is a method of treating or preventing UV-induced aging of the skin in a subject. The method comprises contacting the subject with any of the compositions disclosed herein. 
     An additional embodiment of the present invention is a method of treating or preventing sunburn in a subject. The method comprises contacting the subject with any of the compositions disclosed herein. 
     A further embodiment of the present invention is a method of treating or preventing UV-induced hyperpigmentation in a subject. The method comprises contacting the subject with any of the compositions disclosed herein. 
     Another embodiment of the present invention is a method for brightening skin in a subject. The method comprises contacting the subject with any of the compositions disclosed herein. 
     An additional embodiment of the present invention is a method for inducing melanocyte apoptosis in a subject. The method comprises contacting the subject with any of the compositions disclosed herein. 
     A further embodiment of the present invention is a method for modulating arylhydrocarbon receptor (AhR) activity in a subject. The method comprises contacting the subject with any of the compositions disclosed herein. 
     Another embodiment of the present invention is a method for modulating melanogenesis in a subject. The method comprises contacting the subject with any of the compositions disclosed herein. 
     An additional embodiment of the present invention is a method for modulating melanin concentration in a subject. The method comprises contacting the subject with any of the compositions disclosed herein. 
     Definitions 
     As used herein, the term “compound” refers to two or more atoms that are connected by one or more chemical bonds. In the present invention, chemical bonds include, but are not limited to, covalent bonds, ionic bonds, hydrogen bonds, and van der Waals interactions. Covalent bonds of the present invention include single, double, and triple bonds. Compounds of the present invention include, but are not limited to, organic molecules. 
     Organic compounds/molecules of the present invention include linear, branched, and cyclic hydrocarbons with or without functional groups. The term “C x-y ” when used in conjunction with a chemical moiety, such as, alkyl, alkenyl, alkynyl or alkoxy is meant to include groups that contain from x to y carbons in the chain. For example, the term “C x-y  alkyl” means substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, and the like. The terms “C x-y  alkenyl” and “C x-y  alkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but containing at least one double or triple bond, respectively. 
     The term “aliphatic”, as used herein, means a group composed of carbon and hydrogen atoms that does not contain aromatic rings. Accordingly, aliphatic groups include alkyl, alkenyl, alkynyl, and carbocyclyl groups. 
     As used herein, the term “alkyl” means acyclic linear and branched hydrocarbon groups, e.g. “C 1 -C 20  alkyl” refers to alkyl groups having 1-20 carbons. An alkyl group may be linear or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl tert-pentylhexyl, Isohexyl, and the like. Other alkyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure. An alkyl group may be unsubstituted or substituted with one or more substituent groups as described herein. For example, an alkyl group may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, —CO 2 R′, —COOH, —CN, —OH, —OR′, —NH 2 , —NHR′, —N(R′) 2 , —SR′ or —SO 2 R′, wherein each instance of R′ independently is C 1 -C 3  alkyl. In embodiments, the alkyl is unsubstituted. In embodiments, the alkyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituent groups as described herein). For example, the term “hydroxyalkyl” refers to an alkyl group as described herein comprising a hydroxyl (—OH) substituent and includes groups such as —CH 2 OH. 
     As used herein, “alkenyl” means any linear or branched hydrocarbon chains having one or more unsaturated carbon-carbon double bonds that may occur in any stable point along the chain, e.g. “C 2 -C 20  alkenyl” refers to an alkenyl group having 2-20 carbons. For example, an alkenyl group includes prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, hex-5-enyl, 2,3-dimethylbut-2-enyl, and the like. In embodiments, the alkenyl comprises 1, 2, or 3 carbon-carbon double bonds. In embodiments, the alkenyl comprises a single carbon-carbon double bond. In embodiments, multiple double bonds (e.g., 2 or 3) are conjugated. An alkenyl group may be unsubstituted or substituted with one or more substituent groups as described herein. For example, an alkenyl group may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, —CO 2 R′, —CN, —OH, —OR′, —NH 2 , —NHR′, —N(R′) 2 , —SR′ or —SO 2 R′, wherein each instance of R′ independently is C 1 -C 3  alkyl. In embodiments, the alkenyl is unsubstituted. In embodiments, the alkenyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituent groups as described herein). 
     As used herein, “alkynyl” means any hydrocarbon chain of either linear or branched configuration, having one or more carbon-carbon triple bonds occurring in any stable point along the chain, e.g. “C 2 -C 20  alkynyl” refers to an alkynyl group having 2-20 carbons. Examples of an alkynyl group include prop-2-ynyl, but-2-ynyl, but-3-ynyl, pent-2-ynyl, 3-methylpent-4-ynyl, hex-2-ynyl, hex-5-ynyl, and the like. In embodiments, an alkynyl comprises one carbon-carbon triple bond. An alkynyl group may be unsubstituted or substituted with one or more substituent groups as described herein. For example, an alkynyl group may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, —CO 2 R′, —CN, —OH, —OR′, —NH 2 , —NHR′, —N(R′) 2 , —SR′ or —SO 2 R′, wherein each instance of R′ independently is C 1 -C 3  alkyl. In embodiments, the alkynyl is unsubstituted. In embodiments, the alkynyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituent groups as described herein). 
     As used herein, the term “cycloalkyl” means a nonaromatic, saturated, cyclic group, e.g. “C 3 -C 10  cycloalkyl.” In embodiments, a cycloalkyl is monocyclic. In embodiments, a cycloalkyl is polycyclic (e.g., bicyclic or tricyclic). In polycyclic cycloalkyl groups, individual rings can be fused, bridged, or spirocyclic. Examples of a cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornanyl, bicyclo[3.2.1]octanyl, octahydro-pentalenyl, and spiro[4.5]decanyl, and the like. The term “cycloalkyl” may be used interchangeably with the term “carbocycle”. A cycloalkyl group may be unsubstituted or substituted with one or more substituent groups as described herein. For example, a cycloalkyl group may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, —CO 2 R′, —CN, —OH, —OR′, —NH 2 , —NHR′, —N(R′) 2 , —SR′ or —SO 2 R′, wherein each instance of R′ independently is C 1 -C 3  alkyl. In embodiments, the cycloalkyl is unsubstituted. In embodiments, the cycloalkyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituent groups as described herein). 
     As used herein, the term “halogen” means fluorine, chlorine, bromine, or iodine. 
     As used herein, an “aromatic compound”, “aromatic”, or compound containing an “aromatic ring” is an aryl or a heteroaryl compound. The term “aryl” as used herein includes substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 3- to 8-membered ring, more preferably a 6-membered ring. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. The term “heteroaryl” includes substituted or unsubstituted aromatic single ring structures, preferably 3- to 8-membered rings, more preferably 5- to 7-membered rings, even more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The term “heteroaryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, indole, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Preferably, certain compounds of the present invention include at least one, preferably two, indole groups as well as at least one aldehyde group. 
     The term “substituted” means moieties having at least one substituent that replaces a hydrogen atom on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with the permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, and the like. The permissible substituents can be one or more and the same or different for appropriate organic compounds. 
     As used herein, the term “heterocycle” or “heterocyclic” means a monocyclic, bicyclic, or tricyclic ring system containing at least one heteroatom. Heteroatoms include, but are not limited to, oxygen, nitrogen, and sulfur. 
     A monocyclic heterocyclic ring consists of, for example, a 3, 4, 5, 6, 7, 8, 9, or 10-membered ring containing at least one heteroatom. Representative examples of monocyclic heterocyclic rings include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. 
     A bicyclic heterocyclic ring is, by non-limiting example, a monocyclic heterocyclic ring fused to a distal aryl ring or the monocyclic heterocyclic ring fused to a distal cycloalkyl ring or the monocyclic heterocyclic ring fused to a distal cycloalkenyl ring or the monocyclic heterocyclic ring fused to a distal monocyclic heterocyclic ring, or the monocyclic heterocyclic ring fused to a distal monocyclic heteroaryl ring. Representative examples of bicyclic heterocyclic rings include, but are not limited to, 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-dihydro-1,4-benzodioxinyl, 2,3-dihydro-1-benzofuranyl, 2,3-dihydro-1-benzothienyl, 2,3-dihydro-1H-indolyl, and 1,2,3,4-tetrahydroquinolinyl. 
     A tricyclic heterocyclic ring is, by non-limiting example, a bicyclic heterocyclic ring fused to a phenyl group or the bicyclic heterocyclic ring fused to a cycloalkyl group or the bicyclic heterocyclic ring fused to a cycloalkenyl group or the bicyclic heterocyclic ring fused to another monocyclic heterocyclic ring. Representative examples of tricyclic heterocyclic rings include, but are not limited to, 2,3,4,4a,9,9a-hexahydro-1H-carbazolyl, 5a,6,7,8,9,9a-hexahydrodibenzo[b,d]furanyl, and 5a,6,7,8,9,9a-hexahydrodibenzo[b,d]thienyl. 
     Heterocycles of the present invention can be substituted with substituents independently selected from, by non-limiting example, alkenyl, alkoxy, alkoxyalkyl, alkoxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxy-NH═C(alkyl)-, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkyl, arylcarbonyl, aryloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, carbonyl, cycloalkylalkyl, formyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, hydroxycycloalkyl, mercapto, nitro, oxo, and phenyl. 
     As used herein, “skin pigmentation modulating” and grammatical variations thereof refer generally to skin brightening as well as skin darkening effects of the compounds and compositions of the present invention. 
     As used herein, “skin brightening” and grammatical variations thereof refer generally to any actual or perceived reduction in skin pigmentation. Skin brightening methods have been used to reduce pigmentation of hyperpigmented areas of skin resulting from age, sun exposure, or a hyperpigmentation disorder. Application of the compounds and compositions of the present invention to, for example, a subject&#39;s skin, can reduce pigmentation so that the skin appears lighter or whiter than before said application. Skin pigmentation can be assessed in a number of ways, including, but not limited to, visual assessments using, for example, the von Luschan chromatic scale, the Fitzpatrick skin typing test (Fitzpatrick et al., 1988) and the Taylor Hyperpigmentation Scale (Taylor et al., 2005) and reflectance spectrophotometry methods (Zonios, et al., 2001). For example, the Fitzpatrick skin typing test includes six types of skin (I-VI), and Type VI skin that becomes Type V or less has been “brightened” as the term is used herein. As discussed further below, skin brightening can result due to a number of phenomena, including, but not limited to, modulation of melanocyte activity, induction of melanocyte apoptosis, or modulation of arylhydrocarbon receptor (AhR) activity, melanogenesis, melanosome biogenesis, melanosome transfer, or melanin concentration. 
     Likewise, as used herein, “skin darkening” and grammatical variations thereof refer generally to any actual or perceived increase in skin pigmentation. Skin darkening methods have been used to increase pigmentation of hypopigmented areas of skin resulting from, for example, a hypopigmentation disorder. Application of the compounds and compositions of the present invention to, for example, a subject&#39;s skin, can increase pigmentation so that the skin appears darker than before said application. 
     Certain compounds of the present invention are produced by, derived from, isolated from, or isolatable from a  Malassezia  yeast.  Malassezia  yeasts are yeasts of the genus  Malassezia  and include, but are not limited to,  Malassezia globosa, Malassezia restricta, Malassezia furfur, Malassezia sympodialis, Malassezia slooffiae, Malassezia obtusa, Malassezia pachydermatis, Malassezia dermatis, Malassezia japonica, Malassezia nana, Malassezia yamatoensis, Malassezia equine, Malassezia caprae , and  Malassezia cuniculi . (Guého, et al., 1996; Gaitanis, et al., 2013).  Malassezia  yeast are part of the normal human cutaneous flora and typically produce no pathogenic effects. However,  Malassezia  yeast can cause a number of diseases, including, but not limited to pityriasis versicolor (both the hyperpigmented and hypopigmented varieties), seborrheic dermatitis, dandruff, atopic dermatitis,  Malassezia  folliculitis, psoriasis, and confluent and reticulated papillomatosis. (Gaitanis, et al., 2013). 
     As used herein, the term “chemical analog” refers to a compound that is structurally related to a parent compound and contains different functional groups or substituents. For example, a parent compound of the present invention is indirubin, and chemical analogs of indirubin contain certain functional groups and substituents that are distinct from indirubin. Chemical analogs of the present invention may have significant advantages over a given parent compound, including a pharmacokinetic profile suitable for cosmetic or pharmaceutical use. In some embodiments, a chemical analog is generated from a parent molecule by one or more chemical reactions. In other embodiments, alternative synthesis schemes that do not originate with a parent compound can be used to generate chemical analogs of the present invention. 
     A compound of the present invention is produced by a  Malassezia  yeast if, over the course of its lifecycle, a  Malassezia  yeast would synthesize, secrete, accumulate, or otherwise generate the compound under appropriate growth conditions.  Malassezia  yeast secrete different compounds depending on what their growth media is supplemented with. (Nazzaro-Porro, et al., 1978). The present invention includes any compound produced by a  Malassezia  yeast under any growth condition, but preferred compounds include, for example, malassezin, indirubin, and chemical analogs thereof. 
     A compound of the present invention is derived from a  Malassezia  yeast if, at any time over the course of the yeast&#39;s lifecycle, the compound existed on or in the yeast. 
     Indirubin is one example of a compound produced by a  Malassezia  yeast of the present invention. Indirubin is a metabolite isolated from  Malassezia furfur . Indirubin is a known agonist of the arylhydrocarbon receptor (AhR), a receptor implicated in cell growth, differentiation, and gene expression. 
     As used herein, the term “melanocyte” refers to a dendritic cell of the epidermis that normally synthesizes tyrosinase and, within melanosomes, the pigment melanin. Melanocytes of the present invention exhibit upregulation of certain genes, including, but not limited to, one or more of the following: tyrosinase (oculocutaneous albinism IA), microphthalmia-associated transcription factor, alpha-2-macroglobulin, tyrosinase-related protein 1, solute carrier family 16, GS3955 protein, v-kit Hardy-Zuckerman 4 feline sarcoma, ocular albinism 1, Rag D protein, glycogenin 2, G-protein-coupled receptor, family C, oculocutaneous albinism IL, deleted in esophageal cancer 1, melan-A, SRY-box 10, ATPase, Class V, type 10C, matrix metalloproteinase 1, latent transforming growth factor beta b, ATP-binding cassette, sub-family C, hydroxyprostaglandin dehydrogenase 15, transmembrane 7 superfamily member 1, glutaminyl-peptide cyclotransferase, and other genes identified by Lee and colleagues. (Lee, et al., 2013). 
     Melanocytes, like many other cell types, undergo programmed cell death or, apoptosis. Melanocyte apoptosis pathways are known to those of skill in the art (Wang, et al., 2014), and apoptosis pathways generally have been reviewed by Elmore (Elmore, 2007). A compound or composition of the present invention “induces” melanocyte apoptosis by, for example, causing the activation of certain pro-apoptotic signal transduction pathways or causing the repression of certain anti-apoptotic pathways in a melanocyte. It is envisioned that the compounds or compositions of the present invention can directly activate/repress an apoptosis-related pathway by directly interacting with a signaling molecule of the pathway or by indirectly interacting with a molecule of the pathway via direct interaction with one or more intermediary molecules that do not typically function within the pathway. 
     Melanocyte activity can be modulated in a number of ways contemplated in the present invention, including, but not limited to, inducing melanocyte apoptosis or altering melanocyte gene expression, cell motility, cell growth, melanin production, melanosome biogenesis, or melanosome transfer. 
     As used herein, the terms “modulate”, “modulating”, and grammatical variations thereof refer to an adjustment of a biological activity or phenomenon to a desired level. It is envisioned that “modulation” of the present invention includes adjustments that increase or decrease the levels of the biological activity or phenomenon. 
     As used herein, the terms “agonist”, “agonizing”, and grammatical variations thereof refer to a molecule that triggers (e.g., initiates or promotes), partially or fully enhances, stimulates or activates one or more biological activities. Agonists of the present invention may interact with and activate a receptor, thereby initiating a physiological or pharmacological response characteristic of that receptor. Agonists of the present invention include naturally occurring substances as well as synthetic substances. 
     As used herein, the terms “antagonist”, “antagonizing”, and grammatical variations thereof refer to a molecule that partially or fully suppresses, inhibits, or deactivates one or more biological activities. Antagonists of the present invention may competitively bind to a receptor at the same site as an agonist, but does not activate the intracellular response initiated by the active form of the receptor. Antagonists of the present invention may inhibit intracellular responses of an agonist or partial agonist. 
     An arylhydrocarbon receptor (AhR) of the present invention is any arylhydrocarbon receptor that naturally exists in a subject as described herein. Arylhydrocarbon receptors are known to those of skill in the art. (Noakes, 2015). Agonists of arylhydrocarbon receptors include, but are not limited to, tryptophan-related compounds such as kynurenine, kynurenic acid, cinnabarinic acid, and 6-formylindolo [3,2-b] carbazole (FICZ). 
     As used herein, the compounds, compositions, and methods of the present invention can be used to improve hyperpigmentation caused by a hyperpigmentation disorder by, for example, reducing the level of hyperpigmentation in areas affected by a hyperpigmentation disorder, slowing further hyperpigmentation, or preventing further hyperpigmentation from occurring. However, because every subject may not respond to a particular dosing protocol, regimen, or process, improving hyperpigmentation caused by a hyperpigmentation disorder does not require that the desired physiologic response or outcome be achieved in each and every subject or subject population. Accordingly, a given subject or subject population may fail to respond or respond inadequately to dosing, but other subjects or subject populations may respond and, therefore, experience improvement in their hyperpigmentation disorder. 
     Melanin is a naturally produced pigment that gives color to skin and hair. Melanin is produced by melanocytes in organelles known as melanosomes by a process known as melanogenesis. A compound or composition of the present invention modulates melanin production (a/k/a melanogenesis) in a subject by, for example, modulating melanosome biogenesis and directly or indirectly inhibiting melanin synthesis at the enzymatic level. 
     Melanosome biogenesis occurs via four stages: Stage I is characterized by pre-melanosomes, which are essentially non-pigmented vacuoles. In stage II, pre-melanosomes develop striations on which melanin is deposited in stage III. Stage IV results in mature melanosomes that are rich in melanin content. Compounds and compositions of the present invention modulate melanosome biogenesis by inhibiting or attenuating the biological processes that normally promote any or all of these stages. (Wasmeier, et al., 2008). 
     Melanin synthesis primarily involves three enzymes: tyrosinase, tyrosinase related protein-1, and dopachrome tautomerase. Additional factors that affect intracellular trafficking of these enzymes include, but are not limited to, BLOC-1, OA1, and SLC45A2. The compounds and compositions of the present invention can modulate melanin production by, for example, inhibiting or attenuating the activity of any of these enzymes or factors. (Yamaguchi, et al., 2014). 
     Once melanosomes have formed and melanin has been synthesized, melanosomes need to be transferred from epidermal melanocytes to skin and hair keratinocytes. Melanosomes originate near the nucleus of melanocytes and are transported to the periphery of melanocytes along microtubules and actin filaments. Compounds and compositions of the present invention modulate melanosome transfer by interfering with any of the biological processes that result in the transport of melanosomes from the perinuclear region, to the melanocyte periphery, and into adjacent keratinocytes. 
     Melanin concentration may be modulated by, for example, increasing or decreasing melanogenesis or promoting melanin degradation in, or elimination from, a subject. 
     As used herein, the term “epidermal melanin” refers to melanin that is produced in, transported to, or otherwise found in the epidermis. 
     As used herein, the term “reduce” and grammatical variations thereof mean to cause a decrease in the level of a given biological phenomenon or species. For example, compounds and compositions of the present invention reduce epidermal melanin in a subject, meaning that the compounds and compositions of the present invention elicit a decrease in the level of epidermal melanin in the subject. The term “reduce” and grammatical variations thereof can mean, for example, decreasing the level of a given phenomenon or species by at least 5%, 10%, 25%, 50%, 75%, or 100%. 
     As used herein, the term “contacting” and grammatical variations thereof refer to bringing two or more materials into close enough proximity that they can interact. Thus, for illustrative purposes only, a compound of the present invention can contact a melanocyte by, for example, interacting with a receptor on the surface of the melanocyte. Similarly, a composition of the present invention can contact a human subject by, for example, being applied directly to the subject&#39;s skin. 
     As used herein, a “subject” means a mammalian cell, tissue, organism, or populations thereof. Subjects of the present invention are preferably human, including human cells, tissues, and beings, but otherwise include, primates, farm animals, domestic animals, laboratory animals, and the like. Some examples of agricultural animals include cows, pigs, horses, goats, and the like. Some examples of domestic animals include dogs, cats, and the like. Some examples of laboratory animals include primates, rats, mice, rabbits, guinea pigs, and the like. 
     As used herein, a subject “in need” of improvement in hyperpigmentation caused by a hyperpigmentation disorder includes subjects with a real or perceived need of improvement. 
     As used herein, the terms “treat,” “treating,” “treatment” and grammatical variations thereof mean subjecting an individual subject to a protocol, regimen, process or remedy, in which it is desired to obtain a physiologic response or outcome in that subject, e.g., a patient. In particular, the methods and compositions of the present invention may be used to slow the development of disease symptoms or delay the onset of the disease or condition, or halt the progression of disease development. However, because every treated subject may not respond to a particular treatment protocol, regimen, process or remedy, treating does not require that the desired physiologic response or outcome be achieved in each and every subject or subject population, e.g., patient population. Accordingly, a given subject or subject population, e.g., patient population may fail to respond or respond inadequately to treatment. 
     As used herein, the terms “prevent,” “preventing,” “prevention,” and grammatical variations thereof mean that the compounds of the present invention are useful when administered to a patient who has not been diagnosed as possibly having the disorder or disease at the time of administration, but who would normally be expected to develop the disorder or disease or be at increased risk for the disorder or disease. The compounds and compositions of the invention, for example, slow the development of the disorder or disease symptoms, delay the onset of the disorder or disease, or prevent the individual from developing the disorder or disease at all. Preventing also includes administration of the compounds of the invention to those individuals thought to be predisposed to the disorder or disease due to age, familial history, genetic or chromosomal abnormalities, and/or due to the presence of one or more biological markers for the disorder or disease. 
     As used herein, the term “promote” and grammatical variations thereof mean to allow, enhance, permit, facilitate, foster, encourage, induce, or otherwise help to bring about. 
     As used herein, the term “produce” and grammatical variations thereof mean to cause a particular result to happen, occur, or come into existence. By non-limiting example, the compounds and compositions of the present invention produce a photoprotective or UV-protective effect in a subject. 
     As used herein, the term “erythema” refers to redness of the skin. Erythema may be caused by dilation and/or irritation of the superficial capillaries. The term “UV-induced erythema” refers to skin redness that develops as a result of UV exposure. As used herein, “sunburn” and grammatical variations thereof refers to UV-induced erythema caused by exposure to sunlight or artificial UV sources (e.g. tanning beds). 
     As used herein, the term “hyperpigmentation” refers generally to an area of skin wherein the pigmentation is greater than that of an adjacent area of skin (e.g. a pigment spot, age spot, mole, and the like). Hyperpigmentation of the present invention includes, but is not limited to, regional hyperpigmentation by melanocytic hyperactivity, other localized hyperpigmentation by benign melanocytic hyperactivity and proliferation, disease-related hyperpigmentation, and accidental hyperpigmentations such as those due to photosensitization, genetic makeup, chemical ingestion, or other exposure (e.g. UV exposure), age, and post-lesional scarring. As used herein, “UV-induced hyperpigmentation” refers to any hyperpigmentation caused by exposure to natural or artificial UV. 
     As used herein, the term “hypopigmentation” refers generally to an area of skin wherein the pigmentation is less than that of an adjacent area of skin. Hypopigmentation of the present invention includes, but is not limited to, vitiligo, depigmentation, pityriasis alba, focal hypopigmentation, post-inflammatory hypopigmentation, piebaldism, albinism, tinea versicolor, photosensitivity, leucism, hypomelanosis, atopic dermatitis, psoriasis, and the like. 
     As used herein, “UV-induced skin damage” means skin damage resulting from exposure to UV, including UVA, UVB, and UVC. UV-induced skin damage of the present invention includes, but is not limited to, wrinkles, hyperpigmentation, dysplasias, actinic keratosis, and skin cancers. 
     As used herein, “UV-induced aging of the skin” means skin aging resulting from exposure to UV, including UVA, UVB, and UVC. UV-induced skin aging of the present invention manifests itself as, for example, wrinkles, fine lines, age spots, moles, dryness, thinness, or reduced elasticity of the skin, uneven skin tone, and other reductions in skin radiance, texture, resiliency, firmness, sagginess, and clarity caused, in whole or in part, by UV exposure. 
     As used herein, the term “photoprotective” and grammatical variations thereof, when used to describe the effects of the compounds and compositions of the present invention, mean that the compound and compositions described herein prevent and/or mitigate damage caused by light, particularly sunlight. Likewise, “photoprotective agents” of the present invention are those compounds and compositions described herein that prevent and/or mitigate damage caused by light, particularly sunlight. 
     As used herein, the term “UV-protective” and grammatical variations thereof, when used to describe the effects of the compounds and compositions of the present invention, mean that the compound and compositions described herein prevent and/or mitigate damage caused by ultraviolet (“UV”) light. Likewise, “UV-protective agents” of the present invention are those compounds and compositions described herein that prevent and/or mitigate damage caused by UV. Ultraviolet light of the present invention includes, for example, UVA (320-240 nm), UVB (290-320 nm), and UVC (200-290 nm). 
     As used herein, the term “filter” and grammatical variations thereof mean to block, reflect, absorb, or scatter UV. “Sunscreening agents” of the present invention include all compounds and compositions of the present invention that block, reflect, absorb, or scatter UV. 
     As used herein, the term “absorb” and grammatical variations thereof mean to take in UV or convert UV into heat energy. By non-limiting example, compounds and compositions of the present invention can absorb UV and, as a result, radiate heat energy into their surroundings. 
     As used herein, the term “reflect” and grammatical variations thereof, when used in the context of UV, mean to throw or bounce UV back without absorbing it. 
     As used herein, the term “composition” means an entity comprising one or more compounds of the present invention, as well as any entity which results, directly or indirectly, from combinations of one or more compounds of the present invention with other ingredients. Compositions of the present invention can be used as, for example, in vitro or in vivo research reagents. Compositions of the present invention can also be applied directly to the skin of a human or non-human subject for a cosmetic or pharmaceutical effect. Additionally, compositions of the present invention comprise one or more of the compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. 
     A composition of the present invention may be administered in any desired and effective manner for both in vitro and in vivo applications: for oral ingestion or for parenteral or other administration in any appropriate manner such as intraperitoneal, subcutaneous, topical, intradermal, inhalation, intrapulmonary, rectal, vaginal, sublingual, intramuscular, intravenous, intraarterial, intrathecal, or intralymphatic. Further, a composition of the present invention may be administered in conjunction with other compositions. A composition of the present invention may be encapsulated or otherwise protected against gastric or other secretions, if desired. 
     The compositions of the invention comprise one or more active ingredients in admixture with one or more cosmetically or pharmaceutically acceptable carriers and, optionally, one or more other compounds, ingredients and/or materials. Regardless of the route of administration selected, the compounds and compositions of the present invention are formulated into cosmetically or pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art. 
     Cosmetically or pharmaceutically acceptable vehicles, diluents and carriers are well known in the art and include materials suitable for contact with the tissues of humans and non-humans without undue toxicity, incompatibility, instability, irritation, allergic response and the like. Cosmetically or pharmaceutically acceptable vehicles, diluents and carriers include any substantially non-toxic substance conventionally usable, for example, for topical, oral, peritoneal, or subcutaneous administration of cosmetics or pharmaceuticals in which the compounds and compositions of the present invention will remain stable and bioavailable when applied, ingested, injected, or otherwise administered to a human or non-human subject. Cosmetically or pharmaceutically acceptable carriers suitable for topical application are known to those of skill in the art and include cosmetically or pharmaceutically acceptable liquids, creams, oils, lotions, ointments, gels, or solids, such as conventional cosmetic night creams, foundation creams, suntan lotions, sunscreens, hand lotions, make-up and make-up bases, masks and the like. Carriers suitable for a selected dosage form and intended route of administration are well known in the art, and acceptable carriers for a chosen dosage form and method of administration can be determined using ordinary skill in the art. 
     The compositions of the present invention can contain other ingredients conventional in cosmetics including perfumes, estrogen, Vitamins A, C and E, alpha-hydroxy or alpha-keto acids such as pyruvic, lactic or glycolic acids, lanolin, vaseline, aloe vera, methyl or propyl paraben, pigments and the like. Non-limiting cosmetically or pharmaceutically acceptable vehicles, diluents and carriers of the present invention include sugars (e.g., lactose, sucrose, mannitol, and sorbitol), starches, cellulose preparations, calcium phosphates (e.g., dicalcium phosphate, tricalcium phosphate and calcium hydrogen phosphate), sodium citrate, water, aqueous solutions (e.g., saline, sodium chloride injection, Ringer&#39;s injection, dextrose injection, dextrose and sodium chloride injection, lactated Ringer&#39;s injection), alcohols (e.g., ethyl alcohol, propyl alcohol, and benzyl alcohol), polyols (e.g., glycerol, propylene glycol, and polyethylene glycol), organic esters (e.g., ethyl oleate and triglycerides), biodegradable polymers (e.g., polylactide-polyglycolide, poly(orthoesters), and poly(anhydrides)), elastomeric matrices, liposomes, microspheres, oils (e.g., corn, germ, olive, castor, sesame, cottonseed, and groundnut), cocoa butter, waxes (e.g., suppository waxes), paraffins, silicones, talc, silicylate, and the like. 
     The compositions of the invention may, optionally, contain additional ingredients and/or materials commonly used in cosmetic compositions. These ingredients and materials are well known in the art and include, for example, (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, hydroxypropylmethyl cellulose, sucrose and acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, and sodium lauryl sulfate; (10) suspending agents, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth; (11) buffering agents; (12) excipients, such as lactose, milk sugars, polyethylene glycols, animal and vegetable fats, oils, waxes, paraffins, cocoa butter, starches, tragacanth, cellulose derivatives, polyethylene glycol, silicones, bentonites, silicic acid, talc, salicylate, zinc oxide, aluminum hydroxide, calcium silicates, and polyamide powder; (13) inert diluents, such as water or other solvents; (14) preservatives; (15) surface-active agents; (16) dispersing agents; (17) control-release or absorption-delaying agents, such as hydroxypropylmethyl cellulose, other polymer matrices, biodegradable polymers, liposomes, microspheres, aluminum monostearate, gelatin, and waxes; (18) opacifying agents; (19) adjuvants; (20) wetting agents; (21) emulsifying and suspending agents; (22), solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan; (23) propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane; (24) antioxidants; (25) agents which render the formulation isotonic with the blood of the intended recipient, such as sugars and sodium chloride; (26) thickening agents; (27) coating materials, such as lecithin; and (28) sweetening, flavoring, coloring, perfuming and preservative agents. Each such ingredient or material must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. Ingredients and materials suitable for a selected dosage form and intended route of administration are well known in the art, and acceptable ingredients and materials for a chosen dosage form and method of administration may be determined using ordinary skill in the art. 
     Compositions of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, powders, granules, a solution or a suspension in an aqueous or non-aqueous liquid, an oil-in-water or water-in-oil liquid emulsion, an elixir or syrup, a pastille, a bolus, an electuary or a paste. These formulations may be prepared by methods known in the art, e.g., by means of conventional pan-coating, mixing, granulation or lyophilization processes. 
     Solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like) may be prepared, e.g., by mixing the active ingredient(s) with one or more cosmetically or pharmaceutically acceptable carriers and, optionally, one or more fillers, extenders, binders, humectants, disintegrating agents, solution retarding agents, absorption accelerators, wetting agents, absorbents, lubricants, and/or coloring agents. Solid compositions of a similar type may be employed as fillers in soft and hard-filled gelatin capsules using a suitable excipient. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using a suitable binder, lubricant, inert diluent, preservative, disintegrant, surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine. The tablets, and other solid dosage forms, such as capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the cosmetic formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein. They may be sterilized by, for example, filtration through a bacteria-retaining filter. These compositions may also optionally contain opacifying agents and may be of a composition such that they release the active ingredient only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. The active ingredient can also be in microencapsulated form. 
     Liquid dosage forms for oral administration include cosmetically or pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. The liquid dosage forms may contain suitable inert diluents commonly used in the art. Besides inert diluents, the oral compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents. Suspensions may contain suspending agents. 
     Compositions of the present invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more active ingredient(s) with one or more suitable nonirritating carriers which are solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound. Compositions of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such cosmetically or pharmaceutically acceptable carriers as are known in the art to be appropriate. 
     Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, drops, emulsions, suspensions, aerosols, and inhalants. Any desired conventional vehicles, assistants and optionally further active ingredients may be added to the formulation. 
     Preferred assistants originate from the group comprising preservatives, antioxidants, stabilisers, solubilisers, vitamins, colorants, odour improvers, film formers, thickeners and humectants. 
     Solutions and emulsions can comprise the conventional vehicles, such as solvents, solubilisers and emulsifiers, for example water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol, oils, in particular cottonseed oil, groundnut oil, maize oil, olive oil, castor oil and sesame oil, glycerol fatty acid esters, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances. 
     The emulsions may exist in various forms. Thus, they can be, for example, an emulsion or microemulsion of the water-in-oil (W/O) type or of the oil-in-water (O/W) type, or a multiple emulsion, for example of the water-in-oil-in-water (W/O/W) type. 
     The compositions according to the invention may also be in the form of emulsifier-free, disperse preparations. They can be, for example, hydrodispersions or Pickering emulsions. 
     Suspensions may comprise conventional vehicles, such as liquid diluents, for example water, ethanol or propylene glycol, suspension media, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters and polyoxyethylene sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances. 
     Pastes, ointments, gels and creams may comprise conventional vehicles, for example animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures of these substances. 
     Face and body oils may comprise the conventional vehicles, such as synthetic oils, such as fatty acid esters, fatty alcohols, silicone oils, natural oils, such as vegetable oils and oily plant extracts, paraffin oils, lanolin oils, or mixtures of these substances. 
     Sprays may comprise the conventional propellants, for example chlorofluorocarbons, propane/butane or dimethyl ether. 
     Compositions of the present invention suitable for parenteral administrations comprise one or more compounds in combination with one or more cosmetically or pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain suitable antioxidants, buffers, solutes which render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents. Proper fluidity can be maintained, for example, by the use of coating materials, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain suitable adjuvants, such as wetting agents, emulsifying agents and dispersing agents. It may also be desirable to include isotonic agents. In addition, prolonged absorption of the injectable cosmetic form may be brought about by the inclusion of agents which delay absorption. 
     In some cases, in order to prolong the effect, it is desirable to slow its absorption from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. 
     The rate of absorption of the active agent/drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered composition may be accomplished by dissolving or suspending the active composition in an oil vehicle. Injectable depot forms may be made by forming microencapsule matrices of the active ingredient in biodegradable polymers. Depending on the ratio of the active ingredient to polymer, and the nature of the particular polymer employed, the rate of active ingredient release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue. The injectable materials can be sterilized for example, by filtration through a bacterial-retaining filter. 
     The compositions of the present invention may be presented in unit-dose or multi-dose sealed containers, for example, ampules and vials, and may be stored in a lyophilized condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the type described above. 
     Certain embodiments of the composition of the invention include topical compositions such as, but not limited to, lotions, creams, gels, ointments, serums and salves. In various embodiments, the composition of the invention may be an oil-in-water emulsion or a water-in-oil emulsion, or an oil-based non-emulsion composition. In various embodiments, such a topical composition comprises, optionally together with other ingredients, malassezin or a malassezin analog, such as any of the malassezin analogs described herein, or comprises any compound listed in Table 1 or  FIG. 3 , at a w/w concentration of from 0.01% to 3%, preferably from 0.1% to 2%, such as 0.1%, 0.5%, 1%, 1.5%, or 2%, or a range between any two such concentrations. The composition may further comprise either or both of a suitable solvent, such as dimethyl isosorbide, at a w/w concentration of from 5% to 30%, preferably from 10% to 20%, such as 5%, 10%, 15%, or 20%, or a range between any two such concentrations, and a suitable skin penetrant, such as pentylene glycol, at a w/w concentration of from 0.25% to 2%, preferably from 0.5% to 2%, such as 0.5%, 1%, 1.5%, or 2%, or a range between any two such concentrations. The topical compositions of the invention optionally further comprise other conventional ingredients, such as pharmaceutically or cosmetically acceptable excipients, known to the person of ordinary skill in the art, such as, but not limited to, one or more of an emulsifying agent, emmolient, humectant, solvent (e.g. water), emulsion stabilizer, skin penetrant, preservative, and chelating agent. In various embodiments, the composition of the invention optionally further comprises more than one item from one or more of these categories, such as two or more different emollients, two or more emulsifying agents, etc. The compositions of the invention optionally further comprise other ingredients that protect or promote or otherwise enhance skin health and/or appearance, such as, but not limited to, one or more sunscreening agents (e.g. titanium dioxide, zinc oxide, avobenzone) and/or one or more exfoliating agents (e.g. alpha- or beta-hydroxyacid, vitamin C), such as conventional such agents known to the person of ordinary skill in the art. 
     In the above-described compositions of the invention, the malassezin, malassezin analog, or compound listed in Table 1 or  FIG. 3 , may be provided, for example, in the form of a pharmaceutically or cosmetically acceptable salt, hydrate, or solvate of the compound. Salts, hydrates and solvates are further described below. 
     The invention further provides methods that comprise the step of administering the composition described above. The method of the invention may comprise administering the composition more than once, such as on a regular schedule, such as one or more times daily, or one or more times in a week. Thus, the invention provides methods of protecting or promoting or otherwise enhancing skin health and/or appearance, such as any of the health and appearance objectives described elsewhere herein. The person of ordinary skill in the art can determine the appropriate dosage and administration regimen by conventional means based on the concentration of the active ingredient or active ingredients in the composition and the condition of the individual to be treated. The invention thus provides, for example, a method of reducing fine lines and wrinkles in the skin of a human subject comprising administering to the human subject a composition of the invention, as described above, for example. The invention further provides, for example, a method of promoting smooth skin in a human subject comprising administering to the human subject a composition of the invention, as described above, for example. The invention further provides, for example, a method of promoting skin brightening in a human subject comprising administering to the human subject a composition of the invention, as described above, for example. 
     The invention further provides compositions for use in preventing or treating the conditions described herein, such as for use in a method of reducing fine lines and wrinkles in the skin of a human subject, promoting smooth skin in a human subject, and promoting skin brightening in a human subject, wherein the method comprises administering the composition as described above to the subject, such as by applying the composition to the subject&#39;s skin. 
     In the present invention, the term “crystalline form” means the crystal structure of a compound. A compound may exist in one or more crystalline forms, which may have different structural, physical, pharmacological, or chemical characteristics. Different crystalline forms may be obtained using variations in nucleation, growth kinetics, agglomeration, and breakage. Nucleation results when the phase-transition energy barrier is overcome, thereby allowing a particle to form from a supersaturated solution. Crystal growth is the enlargement of crystal particles caused by deposition of the chemical compound on an existing surface of the crystal. The relative rate of nucleation and growth determine the size distribution of the crystals that are formed. The thermodynamic driving force for both nucleation and growth is supersaturation, which is defined as the deviation from thermodynamic equilibrium. Agglomeration is the formation of larger particles through two or more particles (e.g., crystals) sticking together and forming a larger crystalline structure. 
     The term “hydrate”, as used herein, means a solid or a semi-solid form of a chemical compound containing water in a molecular complex. The water is generally in a stoichiometric amount with respect to the chemical compound. 
     As used herein, “cosmetically or pharmaceutically acceptable salt” refers to a derivative of the compounds disclosed herein wherein the compounds are modified by making acid or base salts thereof. Examples of cosmetically or pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. For example, such salts include salts from ammonia, L-arginine, betaine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine (2,2′-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol, 2-aminoethanol, ethylenediamine, N-ethyl-glucamine, hydrabamine, 1H-imidazole, lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxy-ethyl)-pyrrolidine, sodium hydroxide, triethanolamine (2,2′,2″-nitrilotris(ethanol)), trometh-amine, zinc hydroxide, acetic acid, 2.2-dichloro-acetic acid, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 2,5-dihydroxybenzoic acid, 4-acetamido-benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, decanoic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, ethylenediamonotetraacetic acid, formic acid, fumaric acid, galacaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutantic acid, glutaric acid, 2-oxo-glutaric acid, glycero-phosphoric acid, glycine, glycolic acid, hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, lysine, maleic acid, (−)-L-malic acid, malonic acid, DL-mandelic acid, methanesulfonic acid, galactaric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, octanoic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionic acid, (−)-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid. Further cosmetically or pharmaceutically acceptable salts can be formed with cations from metals like aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and the like. 
     The cosmetically or pharmaceutically acceptable salts of the present invention can be synthesized from a compound disclosed herein which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. 
     It is envisioned that the compounds and compositions of the present invention may be included in cosmetic or pharmaceutical compositions for both in vitro and in vivo applications. 
     It is envisioned that the compounds and compositions of the present invention, including one or more compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof, may be co-administered to a subject to effectuate the skin pigmentation-modulating purposes of the present invention. 
     It is also envisioned that the compositions of the present invention may comprise one or more compounds listed in Table 1 or  FIG. 3 , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. For example, a composition of the present invention may comprise indirubin or chemical analogs thereof in combination with malassezin or chemical analogs thereof. 
     Additionally, it is envisioned that the compounds of the present invention include compounds produced by  Malassezia , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. Further, it is envisioned that the compositions and methods of the present invention may involve one or more compounds produced by  Malassezia , or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof. For example, compounds produced by, or derived from,  Malassezia  include, but are not limited to, the compounds shown in  FIG. 3 . 
     It is further envisioned that the methods of the present invention may involve co-administering two or more compounds and/or compositions of the present invention to effectuate the skin pigmentation-modulating purposes described herein. 
     Co-administered compounds and compositions of the present invention may, for example, contact a subject at substantially the same time or one after another. 
     The compositions of the present invention containing one or more  Malassezia -derived compounds or chemical analogs thereof may demonstrate synergistic effects over component compounds alone on various efficacy criteria, including, but not limited to, mean tissue viability, melanin concentration, skin brightening, skin darkening, induction of melanocyte apoptosis, and modulation of arylhydrocarbon (AhR) activity, melanogenesis, or melanin concentration. 
     The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. As used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. 
     For recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6,9, and 7.0 are explicitly contemplated. 
     The following examples are provided to further illustrate the methods of the present invention. These examples are illustrative only and are not intended to limit the scope of the invention in any way. 
     EXAMPLES 
     Example 1 
     Compound Designations 
     Table 1 below shows structures and names for compounds of the instant invention. 
     
       
         
           
               
               
               
             
               
                 TABLE 1 
               
               
                   
               
               
                 Compound 
                 Compound 
                   
               
               
                 Code 
                 Name 
                 Structure 
               
               
                   
               
             
            
               
                 CV-8684 
                 Malassezin 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 N/A 
                 Malassezin Precursor 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 CV-8685 
                 Indolo[3,2-b] carbazole 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 CV-8686 
                 Compound I 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 CV-8687 
                 Compound IV 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 CV-8688 
                 Compound II 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 CV-8802 
                 Compound C 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 CV-8803 
                 Compound K 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 CV-8804 
                 Compound A 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 AB12508 
                 Compound E 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 CV-8819 
                 Compound A5 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 AB12509 
                 Compound H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 CV-8877 
                 Compound B 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 N/A 
                 Compound B10 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 AB11644 
                 N/A 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 AB12976 
                 O52 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 AB17011 
                 Malassezia Indole A 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 AB17014 
                 Pityriacitrin 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 AB17151 
                 N/A 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 AB17225 
                 Compound VI 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 AB17227 
                 Malassezialactic Acid 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 AB12507 
                 N/A 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 AB17219 
                 Compound V 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 N/A 
                 FICZ 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 AB17220 
                 Compound VIII 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 AB17221 
                 Compound VII 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 N/A 
                 Indirubin 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 AB17590 
                 N/A 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 AB17653 
                 N/A 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 AB17654 
                 N/A 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 AB17655 
                 N/A 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 AB17656 
                 N/A 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 AB17657 
                 N/A 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 AB17658 
                 N/A 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     Example 2 
     Apoptosis-Inducing Activity of Compositions Containing  Malassezia —Derived Compounds and/or Chemical Analogs Thereof 
     Reagents 
     Alexa Fluor 488 Annexin V/Dead Cell Apoptosis Kit, Fetal Bovine Serum (FBS), 0.25% Trypsin-EDTA (1×), Caspase-Glo 3/7 Assay, RPMI 1640 Medium, Dulbecco&#39;s Modified Eagle Medium, and Antibiotic Antimycotic Solution (100×). 
     The cell lines MeWo (ATCC® HTB-65™), WM115 (ATCC® CRL-1675) and B16F1 (ATCC® CRL-6323) are maintained in the following culture media: culture medium for MeWo and B16F1: DMEM supplemented with 10% FBS; culture medium for WM115: RPMI 1640 supplemented with 10% FBS. 
     Experimental Methods 
     Cells are harvested and the cell number determined using a Countess Cell Counter. The cells are diluted with culture medium to the desired density. The final cell density may be, for example, 4,000 cells/well for 6 hr and 24 hr treatment, and 2,000 cells/well for 48 hr and 72 hr treatment. For the Annexin V assay, 384-well clear-bottom plates (Corning 3712) are employed, whereas 384-well solid white-bottom plates (Corning 3570) are used for the Caspase-Glo assays. All plates are covered with a lid and placed at 37° C. and 5% CO 2  overnight for cell attachment. 
     Test compounds are dissolved in DMSO to 30 mM stock. 10-fold dilutions are performed to generate 3 mM and 0.3 mM concentrations. 0.9 mM Staurosporine is employed as positive control, and DMSO is employed as negative control (NC). 132.5 nL of compounds is transferred from compound source plate to 384-well cell culture plate(s) using liquid handler Echo550. After the indicated incubation time, the plates are removed from the incubator for detection. 
     Test compositions are dissolved DMSO, EPI-100-LLMM, or any appropriate solvent and may be prepared according to the instructions in Tables 2-7 below. Appropriate solvents are well known to those of skill in the art. 
     For the Annexin V assay, plates are removed from the incubator and culture media is removed. Cells are washed twice with 40 uL PBS and 15 uL of pre-mixed Annexin V-FITC and Hoechst 33342 dye working solution are added per well. Plates are incubated at room temperature for 20 minutes, sealed, and centrifuged for 1 minute at 1,000 rpm to remove bubbles. Plates are read using ImageXpress Nano. 
     For the Caspase-Glo assay, plates are removed from the incubator and equilibrated at room temperature for 15 minutes. Caspase-Glo 3/7 reagents also are thawed and equilibrated to room temperature before the experiment. Caspase-Glo reagent is added to the required wells at 1:1 ratio to the culture medium. Plates are incubated at room temperature for 15 minutes and read using EnSpire™ plate reader. Fold induction is calculated according to the following formula: Fold induction=Lum sample /Lum NC . 
     Annexin V Assay and Caspase 3/7 Assay Results 
     It is expected that the compounds and compositions of the present invention, including Compositions #1-5, will induce cell death. Compositions of the present invention are expected to exhibit, for example, more potent apoptosis-inducing activity compared to at least one component compound alone. Likewise, compositions of the present invention are expected to demonstrate, for example, less effective apoptosis-inducing activity compared to at least one component compound alone. Such compositions may have more favorable toxicity profiles compared to more potent compositions. 
     Example 3 
     Cell Viability after Exposure to Compositions Containing  Malassezia —Derived Compounds and/or Chemical Analogs Thereof 
     Reagents 
     CellTiter-Glo® 2.0 assay. 
     Experimental Methods 
     For the CellTiter-Glo assay, test compounds are prepared in 10 mM DMSO solution. Compounds are serially diluted into 12 concentrations. 40 uL of cells from a 100,000 cell/mL suspension are dispensed into each well of a 384-well plate (Corning 3570). Plates are incubated overnight at 37° C., 5% CO 2 , and 95% humidity. Test compounds are added, with DMSO as vehicle control. Plates are incubated at 37° C., 5% CO 2 , and 95% humidity for 6, 24, or 48 hours, and 40 uL of CellTiter-Glo reagent is added to the wells to assess cell viability. 
     Test compositions are dissolved DMSO, EPI-100-LLMM, or any appropriate solvent and may be prepared according to the instructions in Tables 2-7 below. Appropriate solvents are well known to those of skill in the art. 
     Results 
     It is expected that the compounds and compositions of the present invention, including Compositions #1-5, will induce cell death. Compositions of the present invention are expected to exhibit, for example, more potent apoptosis-inducing activity compared to at least one component compound alone. Likewise, compositions of the present invention are expected to demonstrate, for example, less effective apoptosis-inducing activity compared to at least one component compound alone. Such compositions may have more favorable toxicity profiles compared to more potent compositions. 
     Example 4 
     Arylhydrocarbon Receptor Activation Potential of Compositions Containing  Malassezia —Derived Compounds and/or Chemical Analogs Thereof 
     Assay Procedures 
     Culture media for stably transfected HepG2 cells is prepared by supplementing DMEM with high glucose and L-glutamine, as well as 10% FBS. 
     HepG2-AhR-Luc cells are cultured in T-75 flasks at 37° C., 5% CO 2 , and 95% relative humidity. Cells are allowed to reach 80-90% confluence before detachment and splitting. 
     Cultivated cells are rinsed with 5 mL PBS. PBS is aspirated away, 1.5 mL trypsin is added to the flask, and cells are incubated at 37° C. for approximately 5 minutes or until the cells are detached and float. Trypsin is inactivated by adding excess serum-containing media. 
     The cell suspension is transferred to a conical tube and centrifuged at 120 g for 10 minutes to pellet the cells. Cells are resuspended in seeding media at a proper density. 40 μL of cells are transferred to a 384-well culture plate (5×10 3  cells/well). Plates are placed in the incubator at 37° C. for 24 hours. 
     Afterward, stock solutions of test compounds, test compositions, and omeprazole positive control are prepared. Compound and compositions solutions are transferred into the assay plate using Echo550. The plate is then placed back into the incubator for compound/composition treatment. 
     Later, after 24 hours of treatment, the plate is removed from the incubator and allowed to cool at ambient temperature. 30 μL One-Glo reagent equal to that of the culture medium is added in each well. Cells are allowed to lyse for at least 3 minutes, and then measured in a luminometer. 
     Dose responses are graphed using the non-linear regression analysis in XLfit, and EC 50  values are also calculated. 
     Results 
     It is expected that the compounds and compositions of the present invention, including Compositions #1-5, will modulate AhR activity. Compositions of the present invention are expected to exhibit, for example, more potent AhR agonist activity compared to at least one component compound alone. Likewise, compositions of the present invention are expected to demonstrate, for example, less effective AhR agonist activity compared to at least one component compound alone. Compositions of the present invention also are expected to exhibit, for example, more potent AhR antagonist activity compared to at least one component compound alone. Likewise, compositions of the present invention also are expected to demonstrate, for example, less effective AhR antagonist activity compared to at least one component compound alone. 
     Example 5 
     MelanoDerm™ Assays 
     The purpose of this study was to evaluate the potential action of the test articles as a skin melanogenesis modulator in the MelanoDerm™ Skin Model after repeated test article exposures. Secondarily, the purpose of this study was to evaluate the potential dermal irritation of the test article to the MelanoDerm™ Skin Model after repeated exposures. Toxicity was determined by measuring the relative conversion of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) in the test article-treated tissues compared to the negative/solvent control-treated tissues. The potential impact on melanin production was determined by measuring the concentration of melanin produced by the test article-treated tissues compared to the negative/solvent control-treated tissues. 
     Identification of Test Substances and Assay Controls 
       
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Test Articles Tested in Diluted Form 
               
            
           
           
               
               
               
               
            
               
                 Test Article 
                 Sponsor 
                 Dosing 
                   
               
               
                 Designation 
                 Designation 
                 Concentration 
                 Preparation Instructions 
               
               
                   
               
               
                 18AH47 
                 DMSO 
                 0.5% 
                 The solvent control was diluted (v/v) with 
               
               
                   
                 (solvent control) 
                 (v/v) 
                 EPI-100-LLMM to a final concentration of 
               
               
                   
                   
                   
                 0.5%; the diluted solvent control was 
               
               
                   
                   
                   
                 vortexed for at least 1 minute and dosed 
               
               
                   
                   
                   
                 onto the tissues using a dosing volume of 
               
               
                   
                   
                   
                 25 μL. A total volume of up to 0.5 mL was 
               
               
                   
                   
                   
                 prepared for each tissue treatment. 
               
               
                 17AJ41 
                 Malassezin (CV-8684) 
                 500 μM 
                 Starting from the stock concentration 
               
               
                   
                 (Positive control) 
                   
                 provided by the Sponsor/prepared from the 
               
               
                 17AJ55 
                 O52 
                 650 μM 
                 solid material provided by the Sponsor, the 
               
               
                 18AA21 
                   Malassezia  Indole A 
                 650 μM 
                 test article/control was diluted (v/v) with 
               
               
                 18AF50 
                 AB17151 
                 300 μM 
                 EPI-100-LLMM to the dosing 
               
               
                 18AH15 
                 AB17590 
                 300 μM 
                 concentration listed. The test article 
               
               
                 18AH21 
                 AB11644 
                 650 μM 
                 dilution was vortexed for at least 1 minute, 
               
               
                 18AH38 
                 Indole-3-carbaldehyde 
                 500 μM 
                 heated at 37° ± 1° C. (in a water bath) for 15 
               
               
                 18AH39 
                 D-indole-3-lactic acid 
                 500 μM 
                 minutes, vortexed again for at least 1 
               
               
                   
                   
                   
                 minute and dosed on the tissues using a 
               
               
                   
                   
                   
                 dosing volume of 25 μL. A total volume of 
               
               
                   
                   
                   
                 up ~0.5 mL was prepared for each tissue 
               
               
                   
                   
                   
                 treatment. 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Composition #1 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Preparation 
               
               
                   
                   
                 Preparation 
                   
                 Instructions For 
               
               
                   
                   
                 Instructions For 
                   
                 Dilutions Used 
               
               
                 Test Article 
                 Sponsor 
                 Working Stock 
                 Dosing 
                 For Dosing of 
               
               
                 Designation 
                 Designation 
                 Solutions 
                 Concentration 
                 the Tissues 
               
               
                   
               
               
                 17AD42 
                 Indolo-carbazole 
                 A working 
                 The dosing 
                 Fifty (50) μL of 
               
               
                   
                 (ICZ) 
                 stock solution 
                 concentration 
                 each working 
               
               
                   
                   
                 of 360 μM was 
                 of each of the 
                 stock solution 
               
               
                   
                   
                 prepared from 
                 components 
                 was transferred 
               
               
                   
                   
                 the top stock 
                 was 18 μM. 
                 into a new vial 
               
               
                   
                   
                 solution in 
                   
                 (combined 
               
               
                   
                   
                 DMSO as follows: 
                   
                 volume of 700 
               
               
                   
                   
                 The stock solution 
                   
                 μL) and mixed 
               
               
                   
                   
                 was thawed at 
                   
                 with 300 μL of 
               
               
                   
                   
                 room temperature and 
                   
                 EPI-100-LLMM 
               
               
                   
                   
                 vortexed for ~1 
                   
                 to yield 
               
               
                   
                   
                 minute. The 
                   
                 a total volume 
               
               
                   
                   
                 appropriate 
                   
                 of 1000 μL. 
               
               
                   
                   
                 volume needed 
                   
                 The dilution 
               
               
                   
                   
                 to prepare up 
                   
                 was vortexed 
               
               
                   
                   
                 to ~0.5 mL/1.0 
                   
                 for at least 1 
               
               
                   
                   
                   
                   
                 minute before 
               
               
                   
                   
                   
                   
                 being applied 
               
               
                   
                   
                   
                   
                 onto the tissues. 
               
               
                 17AJ41 
                 Malassezin (CV-8684) 
                 mL of working 
               
               
                   
                 (Positive control) 
                 stock solution 
               
               
                   
                   
                 was transferred 
               
               
                   
                   
                 to a new vial 
               
               
                   
                   
                 and diluted with 
               
               
                   
                   
                 EPI-100-LLMM to 
               
               
                   
                   
                 360 μM. The dilution 
               
               
                   
                   
                 was vortexed for at 
               
               
                   
                   
                 least 1 minute, heated at 
               
               
                   
                   
                 37° ± 1° C. 
               
               
                   
                   
                 (in a water bath) for 
               
               
                   
                   
                 15 minutes and 
               
               
                   
                   
                 vortexed again 
               
               
                   
                   
                 for at least 1 
               
               
                   
                   
                 minute before 
               
               
                   
                   
                 being subsequently 
               
               
                   
                   
                 diluted. 
               
               
                 17AJ47 
                 Compound A5 
               
               
                   
                 (also known as 
               
               
                   
                 Keto-Malassezin) 
               
               
                 17AJ55 
                 052 
               
               
                 18AA21 
                   Malassezia  Indole A 
               
               
                 18AA22 
                 Pityriacitrin 
               
               
                 18AA24 
                 FICZ 
               
               
                 18AD42 
                 Indirubin 
               
               
                 18AH16 
                 Trypthantrin 
               
               
                 18AH20 
                   Malassezia -lactic Acid 
               
               
                 18AH24 
                 2-hydroxy-1-(1H-indol-3-yl)ethanone 
               
               
                 18AH38 
                 Indole-3-carbaldehyde 
               
               
                 18AH39 
                 D-Indole-3-lactic acid 
               
               
                 18AH44 
                 (Indol-3-yl)pyruvic acid 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Composition #2 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 Preparation 
               
               
                   
                   
                   
                   
                   
                 Instructions 
               
               
                   
                   
                 Preparation 
                   
                   
                 For Dilutions 
               
               
                   
                   
                 Instructions For 
                   
                   
                 Used For 
               
               
                 Test Article 
                 Sponsor 
                 Working Stock 
                 Dosing 
                 Volume 
                 Dosing of the 
               
               
                 Designation 
                 Designation 
                 Solutions 
                 Concentration 
                 Needed 
                 Tissues 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 17AD42 
                 Indolo-carbazole 
                 A working 
                 12.6 μM 
                 35 
                 The volume 
               
               
                   
                 (ICZ) 
                 stock solution 
                   
                   
                 of the dosing 
               
               
                   
                   
                 of 360 μM was 
                   
                   
                 concentration 
               
               
                   
                   
                 prepared from 
                   
                   
                 listed for each 
               
               
                   
                   
                 the top stock 
                   
                   
                 component was 
               
               
                   
                   
                 solution in 
                   
                   
                 transferred 
               
               
                   
                   
                 DMSO as 
                   
                   
                 into a new 
               
               
                   
                   
                 follows: The 
                   
                   
                 vial and 
               
               
                   
                   
                 stock solution 
                   
                   
                 mixed with 
               
               
                   
                   
                 was thawed at 
                   
                   
                 297 μL of 
               
               
                   
                   
                 room temperature 
                   
                   
                 EPI-100-LLMM. 
               
               
                   
                   
                 and vortexed 
                   
                   
                 The dilution was 
               
               
                   
                   
                 for ~1 minute. 
               
               
                 17AJ41 
                 Malassezin (CV-8684) 
                 The appropriate 
                 50.4 μM 
                 140 
                 vortexed for 
               
               
                   
                 (Positive control) 
                 volume needed 
                   
                   
                 at least 1 
               
               
                   
                   
                 to prepare up 
                   
                   
                 minute before 
               
               
                   
                   
                 to ~0.5 mL/1.0 
                   
                   
                 being applied 
               
               
                   
                   
                 mL of working 
                   
                   
                 onto the 
               
               
                   
                   
                 stock solution 
                   
                   
                 tissues. 
               
               
                   
                   
                 was transferred 
               
               
                   
                   
                 to a new vial 
               
               
                   
                   
                 and diluted 
               
               
                   
                   
                 with EPI-100-LLMM 
               
               
                   
                   
                 to 360 μM. The 
               
               
                   
                   
                 dilution was 
               
               
                   
                   
                 vortexed for at 
               
               
                   
                   
                 least 1 minute, 
               
               
                   
                   
                 heated at 
               
               
                   
                   
                 37°± 1° C. (in a 
               
               
                   
                   
                 water bath) for 
               
               
                   
                   
                 15 minutes and 
               
               
                   
                   
                 vortexed again 
               
               
                   
                   
                 for at least 1 
               
               
                   
                   
                 minute before 
               
               
                 17AJ47 
                 Compound A5 
                 being 
                 10.1 μM 
                 28 
               
               
                   
                 (also known as 
                 subsequently 
               
               
                   
                 Keto-Malassezin) 
                 diluted. 
               
               
                 17AJ55 
                 052 
                   
                 10.1 μM 
                 28 
               
               
                 18AA21 
                 
                   Malassezia 
                 
                   
                 10.1 μM 
                 28 
               
               
                   
                 Indole A 
               
               
                 18AA22 
                 Pityriacitrin 
                   
                 50.4 μM 
                 140 
               
               
                 18AA24 
                 FICZ 
                   
                 10.1 μM 
                 28 
               
               
                 18AD42 
                 Indirubin 
                   
                 24.5 μM 
                 68 
               
               
                 18AH16 
                 Trypthantrin 
                   
                 24.5 μM 
                 68 
               
               
                 18AH20 
                   Malassezia -lactic Acid 
                   
                 10.1 μM 
                 28 
               
               
                 18AH24 
                 2-hydroxy-1-(1H-indol-3-yl)ethanone 
                   
                 10.1 μM 
                 28 
               
               
                 18AH38 
                 Indole-3-carbaldehyde 
                   
                 10.1 μM 
                 28 
               
               
                 18AH39 
                 D-Indole-3-lactic acid 
                   
                 10.1 μM 
                 28 
               
               
                 18AH44 
                 (Indol-3-yl)pyruvic acid 
                   
                 10.1 μM 
                 28 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Composition #3 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 Preparation 
               
               
                   
                   
                 Preparation 
                   
                   
                 Instructions 
               
               
                   
                   
                 Instructions for 
                 Dosing 
                 Volume 
                 for Dilutions 
               
               
                 Test Article 
                 Sponsor 
                 Working Stock 
                 Concentration 
                 Needed 
                 Used for Dosing 
               
               
                 Designation 
                 Designation 
                 Solutions 
                 (μM) 
                 (μL) 
                 of the Tissues 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 17AJ41 
                 Malassezin (CV-8684) 
                 A working 
                 50.4 
                 140 
                 The volume 
               
               
                   
                 (Positive control) 
                 stock solution 
                   
                   
                 of the dosing 
               
               
                   
                   
                 of 360 μM was 
                   
                   
                 concentration 
               
               
                   
                   
                 prepared from 
                   
                   
                 listed for each 
               
               
                 17AD46 
                 Compound A5 (CV-8819) 
                 the top stock 
                 10.1 
                 28 
                 component was 
               
               
                   
                 (also known as Keto- 
                 solution in 
                   
                   
                 transferred 
               
               
                   
                 Malassezin) 
                 DMSO as 
                   
                   
                 into a new 
               
               
                   
                   
                 follows: The 
                   
                   
                 vial and 
               
               
                   
                   
                 stock solution 
                   
                   
                 mixed with 
               
               
                   
                   
                 was thawed at 
                   
                   
                 568 μL of 
               
               
                 17AJ55 
                 O52 (AB12976) 
                 room temperature 
                 10.1 
                 28 
                 EPI-100-LLMM. 
               
               
                   
                   
                 and vortexed 
                   
                   
                 The dilution was 
               
               
                 18AA21 
                   Malassezia  Indole A 
                 for ~1 minute. 
                 10.1 
                 28 
                 vortexed for 
               
               
                   
                 (AB17011) 
                 The appropriate 
                   
                   
                 at least 1 
               
               
                   
                   
                 volume needed 
                   
                   
                 minute 
               
               
                 18AD42 
                 Indirubin 
                 to prepare up 
                 24.5 
                 68 
                 before being 
               
               
                 18AH20 
                 AB17227 (also known as 
                 to ~0.5 mL/1.0 
                 10.1 
                 28 
                 applied onto 
               
               
                   
                 Malassezia-lactic Acid) 
                 mL of working 
                   
                   
                 the tissues. 
               
               
                   
                   
                 stock solution 
               
               
                   
                   
                 was transferred 
               
               
                   
                   
                 to a new vial 
               
               
                 18AH24 
                 2-hydroxy-1-(1H-indol-3-yl)ethanone 
                 and diluted 
                 10.1 
                 28 
               
               
                   
                   
                 with EPI-100-LLMM 
               
               
                   
                   
                 to 360 μM. The 
               
               
                 18AH38 
                 Indole-3-carbaldehyde 
                 dilution was 
                 10.1 
                 28 
               
               
                   
                   
                 vortexed for at 
               
               
                 18AH39 
                 D-Indole-3-lactic acid 
                 least 1 minute, 
                 10.1 
                 28 
               
               
                   
                   
                 heated at 
               
               
                 18AH44 
                 (Indol-3-yl)pyruvic acid 
                 37° ± 1° C. 
                 10.1 
                 28 
               
               
                   
                   
                 (in a water bath) for 
               
               
                   
                   
                 15 minutes and 
               
               
                   
                   
                 vortexed again 
               
               
                   
                   
                 for at least 1 
               
               
                   
                   
                 minute before being 
               
               
                   
                   
                 subsequently diluted. 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Composition #4 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 Preparation 
               
               
                   
                   
                 Preparation 
                   
                   
                 Instructions 
               
               
                   
                   
                 Instructions 
                 Dosing 
                 Volume 
                 for Dilutions 
               
               
                 Test Article 
                 Sponsor 
                 for Working 
                 Concentration 
                 Needed 
                 Used for Dosing 
               
               
                 Designation 
                 Designation 
                 Stock Solutions 
                 (μM) 
                 (μL) 
                 of the Tissues 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 17AD42 
                 CV-8685 (also known 
                 A working 
                 12.6 
                 35 
                 The volume 
               
               
                   
                 as Indolo-carbazole 
                 stock solution 
                   
                   
                 of the dosing 
               
               
                   
                 or ICZ) 
                 of 360 μM was 
                   
                   
                 concentration 
               
               
                   
                   
                 prepared from 
                   
                   
                 listed for each 
               
               
                 17AJ41 
                 Malassezin (CV-8684) 
                 the top stock 
                 50.4 
                 140 
                 component was 
               
               
                   
                 (Positive control) 
                 solution in DMSO 
                   
                   
                 transferred into 
               
               
                   
                   
                 as follows: 
                   
                   
                 a new vial and 
               
               
                 17AD46 
                 Compound A5 (CV-8819) 
                 The stock solution 
                 10.1 
                 28 
                 mixed with 
               
               
                   
                 (also known as Keto- 
                 was thawed at 
                   
                   
                 505 μL of 
               
               
                   
                 Malassezin) 
                 room temperature 
                   
                   
                 EPI-100-LLMM. 
               
               
                   
                   
                 and vortexed 
                   
                   
                 The dilution was 
               
               
                   
                   
                 for ~1 minute. 
                   
                   
                 vortexed for 
               
               
                   
                   
                 The appropriate 
                   
                   
                 at least 1 minute 
               
               
                 17AJ55 
                 O52 (AB12976) 
                 volume needed to 
                 10.1 
                 28 
                 before being 
               
               
                   
                   
                 prepare up to ~0.5 
                   
                   
                 applied onto 
               
               
                 18AA21 
                   Malassezia  Indole A 
                 mL/1.0 mL 
                 10.1 
                 28 
                 the tissues. 
               
               
                   
                 (AB17011) 
                 of working stock 
               
               
                   
                   
                 solution was 
               
               
                   
                   
                 transferred 
               
               
                 18AA24 
                 FICZ 
                 to a new vial 
                 10.1 
                 28 
               
               
                 18AD42 
                 Indirubin 
                 and diluted 
                 24.5 
                 68 
               
               
                 18AH20 
                 AB17227 (also known as 
                 with EPI-100-LLMM 
                 10.1 
                 28 
               
               
                   
                 Malassezia-lactic 
                 to 360 μM. 
               
               
                   
                 Acid) 
                 The dilution 
               
               
                 18AH24 
                 2-hydroxy-1-(1H-indol-3-yl)ethanone 
                 was vortexed for 
                 10.1 
                 28 
               
               
                 18AH38 
                 Indole-3-carbaldehyde 
                 at least 1 
                 10.1 
                 28 
               
               
                 18AH39 
                 D-Indole-3-lactic acid 
                 minute, heated at 
                 10.1 
                 28 
               
               
                 18AH44 
                 (Indol-3-yl)pyruvic acid 
                 37° ± 1° C. (in 
                 10.1 
                 28 
               
               
                   
                   
                 a water bath) for 15 
               
               
                   
                   
                 minutes and vortexed 
               
               
                   
                   
                 again for at least 1 
               
               
                   
                   
                 minute 
               
               
                   
                   
                 before being 
               
               
                   
                   
                 subsequently 
               
               
                   
                   
                 diluted. 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Composition #5 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 Preparation 
               
               
                   
                   
                 Preparation 
                   
                   
                 Instructions 
               
               
                   
                   
                 Instructions 
                 Dosing 
                 Volume 
                 for Dilutions 
               
               
                 Test Article 
                 Sponsor 
                 for Working 
                 Concentration 
                 Needed 
                 Used for Dosing 
               
               
                 Designation 
                 Designation 
                 Stock Solutions 
                 (μM) 
                 (μL) 
                 of the Tissues 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 17AD42 
                 CV-8685 
                 A working 
                 74.9 
                 208 
                 The volume 
               
               
                   
                 (also known 
                 stock solution 
                   
                   
                 of the dosing 
               
               
                   
                 as Indolo-carbazole 
                 of 360 μM was 
                   
                   
                 concentration 
               
               
                   
                 or ICZ) 
                 prepared from 
                   
                   
                 listed for 
               
               
                   
                   
                 the top stock 
                   
                   
                 each component 
               
               
                   
                   
                 solution in DMSO 
                   
                   
                 was transferred 
               
               
                 17AJ41 
                 Malassezin (CV-8684) 
                 as follows: The 
                 10.1 
                 28 
                 into a new 
               
               
                   
                 (Positive 
                 stock solution 
                   
                   
                 vial and 
               
               
                   
                 control) 
                 was thawed at 
                   
                   
                 mixed with 
               
               
                   
                   
                 room temperature 
                   
                   
                 306 μL of 
               
               
                   
                   
                 and vortexed 
                   
                   
                 EPI-100-LLMM. 
               
               
                   
                   
                 for ~1 minute. 
                   
                   
                 The dilution was 
               
               
                   
                   
                 The appropriate 
                   
                   
                 vortexed for at 
               
               
                   
                   
                 volume needed to 
                   
                   
                 least 1 minute 
               
               
                   
                   
                 prepare up to ~0.5 
                   
                   
                 before being 
               
               
                   
                   
                 mL/1.0 mL of working 
                   
                   
                 applied onto 
               
               
                   
                   
                 stock solution was 
                   
                   
                 the tissues. 
               
               
                   
                   
                 transferred 
               
               
                   
                   
                 to a new vial 
               
               
                 18AA22 
                 Pityriacitrin 
                 and diluted 
                 10.1 
                 28 
               
               
                   
                 (AB17014) 
                 with EPI-100-LLMM 
               
               
                 18AA24 
                 FICZ 
                 to 360 μM. 
                 74.9 
                 208 
               
               
                 18AD42 
                 Indirubin 
                 The dilution 
                 24.8 
                 69 
               
               
                 18AH16 
                 Trypthantrin 
                 was vortexed for 
                 10.1 
                 28 
               
               
                 18AH24 
                 2-hydroxy-1-(1H-indol-3-yl)ethanone 
                 at least 1 minute, 
                 10.1 
                 28 
               
               
                 18AH39 
                 D-Indole-3-lactic acid 
                 heated at 
                 24.8 
                 69 
               
               
                 18AH44 
                 (Indol-3-yl)pyruvic acid 
                 37° ± 1° C. 
                 10.1 
                 28 
               
               
                   
                   
                 (in a water bath) 
               
               
                   
                   
                 for 15 minutes and 
               
               
                   
                   
                 vortexed again for at 
               
               
                   
                   
                 least 1 minute before 
               
               
                   
                   
                 being subsequently diluted. 
               
               
                   
               
            
           
         
       
     
     Assay controls include: positive control—malassezin (CV-8684) (500 μM) (17AJ41) and solvent control—DMSO (dimethyl sulfoxide) prepared in EPI-100-LLMM. 
     Additionally, the test article and controls were applied to groups of 4 tissues of which 2 were used for the Tissue Viability (MTT) endpoint and 2 for the Melanin endpoint, respectively. 
     Test System 
     The MelanoDerm™ Skin Model provided by MatTek Corporation (Ashland, Mass.) was used in this study. The MelanoDerm™ tissue consists of normal, human-derived epidermal keratinocytes (NHEK) and melanocytes (NHM) which have been cultured to form a multilayered, highly differentiated model of the human epidermis. The NHMs within co-cultures undergo spontaneous melanogenesis leading to tissues of varying levels of pigmentation. The cultures were grown on cell culture inserts at the air-liquid interface, allowing for topical application of skin modulators. The MelanoDerm™ model exhibits in vivo-like morphological and ultrastructural characteristics. NHM localized in the basal cell layer of MelanoDerm™ tissue are dendritic and spontaneously produce melanin granules which progressively populate the layers of the tissue. Thus the test system is used to screen for materials which may inhibit or stimulate the production of melanin relative to the negative controls. 
     Experimental Design and Methodology 
     The experimental design of this study consisted of the determination of the pH of the neat test article if possible (and/or dosing solution as appropriate) and a definitive assay to determine the relative tissue viability and the potential action of the test article as a skin melanogenesis modulator to MelanoDerm™ Skin Model after repeated exposures. The test articles were exposed to the MelanoDerm™ Skin Model for a total of 7 days. The test articles were topically applied to the MelanoDerm™ Skin Model every 48 hours (within a timeframe of 48±2 hours from previous treatment). The toxicity of the test articles were determined by the NAD(P)H-dependent microsomal enzyme reduction of MTT (and, to a lesser extent, by the succinate dehydrogenase reduction of MTT) in control and test article-treated tissues. Data was presented in the form of relative survival (MTT conversion relative to the negative/solvent control). The potential impact on melanin production was evaluated by determining the concentration of melanin produced in the test article-treated tissues compared to the negative/solvent control-treated tissues. Data was presented in the form of concentration of melanin produced by the test article-treated tissues determined using a melanin standard curve. Alternatively, data may be presented as percent change in melanin concentration relative to the negative/solvent control-treated tissues. 
     The methods used are a modification of the procedures supplied by MatTek Corporation. 
     Media and Reagents 
     MelanoDerm™ Maintenance Medium (EPI-100-LLMM) was purchased from MatTek Corporation. MelanoDerm™ Skin Model (MEL-300-A) was purchased from MatTek Corporation. 1% Kojic acid (prepared in sterile, deionized water) was purchased from Sigma. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) was purchased from Sigma. Dulbecco&#39;s Modified Eagle&#39;s Medium (DMEM) containing 2 mM L-glutamine (MTT Addition Medium) was purchased from Quality Biological. Extraction Solvent (Isopropanol) was purchased from Aldrich. Sterile Ca++ and Mg++ Free Dulbecco&#39;s Phosphate Buffered Saline (CMF-DPBS) was purchased from Invitrogen. Melanin was purchased from Sigma. Sterile deionized water was purchased from Quality Biological. Solvable was purchased from Perkin Elmer. 
     Preparation and Delivery of Test Article 
     Unless otherwise specified within this protocol, twenty five microliters of each test article were applied directly on the tissue so as to cover the upper surface. Depending on the nature of the test article (liquids, gels, creams, foams, and the like), the use of a dosing device, mesh or other aid to allow the uniform spreading of the test article over the surface of the tissue may have been necessary. 
     Route of Administration 
     The test articles were applied topically to the MelanoDerm™ tissue every 48 hours (within a timeframe of 48+2 hours from previous treatment) during a 7-day trial. Twenty five microliters of each test article were applied to each tissue. Twenty five microliters of the positive and negative/solvent controls, respectively, were applied to each tissue. 
     pH Determination 
     The pH of the neat liquid test article (and/or dosing solution as appropriate) was determined, if possible. The pH was determined using pH paper (for example, with a pH range of 0-14 to estimate, and/or a pH range of 5-10 to determine a more precise value). The typical pH increments on the narrower range pH paper were approximately 0.3 to 0.5 pH units. The maximum increment on the pH paper was 1.0 pH units. 
     Controls 
     The definitive assay included a negative control, a positive control and one solvent control (DMSO) or a positive control and a solvent control (DMSO). The MelanoDerm™ tissues designated to the assay negative/solvent control were treated with 25 μL of sterile, deionized water or DMSO. The tissues designated to the assay positive control were treated with 25 μL of 1% Kojic acid, Malassezin (CV-8684) (17AJ41) 500 μM, or Composition #2. The 1% Kojic acid was stored in a tube covered with aluminum foil until used within 2 hours of preparation. The negative/solvent and positive control exposure times were identical to those used for the test articles. Untreated tissues were also used as controls. 
     Assessment of Direct Test Article Reduction of MTT 
     It was necessary to assess the ability of each test article to directly reduce MTT. A 1.0 mg/mL MTT solution was prepared in MTT Addition Medium. Approximately 25 μL of the test article was added to 1 mL of the MTT solution and the mixture was incubated in the dark at 37±1° C. for one to three hours. A negative control, 25 μL of sterile, deionized water, or a solvent control, 25 μL of DMSO was tested concurrently. If the MTT solution color turned blue/purple, the test article was presumed to have reduced the MTT. Water insoluble test materials may have shown direct reduction (darkening) only at the interface between the test article and the medium. 
     Receipt of MelanoDerm™ 
     Upon receipt of the MelanoDerm™ Skin Kit, the solutions were stored as indicated by the manufacturer. The MelanoDerm™ tissues were stored at 2-8° C. until used. 
     On the day of receiving (the day before dosing), an appropriate volume of MelanoDerm™ Maintenance Medium (EPI-100-LLMM) was removed and warmed to 371° C. Nine-tenths (0.9) mL of EPI-100-LLMM/well were aliquoted into the appropriate wells of 6-well plates. Each MelanoDerm™ tissue was inspected for air bubbles between the agarose gel and cell culture insert prior to opening the sealed package. Tissues with air bubbles greater than 50% of the cell culture insert area were not used. The 24-well shipping containers were removed from the plastic bag and the surface disinfected with 70% ethanol. An appropriate number of MelanoDerm™ tissues were transferred aseptically from the 24-well shipping containers into the 6-well plates. The MelanoDerm™ tissues were incubated at 37±1° C. in a humidified atmosphere of 5±1% CO2 in air (standard culture conditions) overnight (at least 16 hours) to acclimate the tissues. Upon opening the bag, any unused tissues remaining on the shipping agar at the time of tissue transfer were briefly gassed with an atmosphere of 5% CO2/95% air, and the bag was sealed and stored at 2-8° C. for subsequent use. 
     Definitive Assay 
     Tissue Exposure: At least 16 hours after initiating the cultures, five MelanoDerm™ tissues (considered untreated at Day 0) were photographed using a digital camera to aid in the visual assessment of the degree of pigmentation of the tissues at time zero of the assay. Two MelanoDerm™ tissues were rinsed with CMF-DPBS, blotted dry on sterile absorbent paper and cleared of excess liquid. The MelanoDerm™ tissues were transferred to the appropriate MTT containing wells after rinsing and processed in the MTT assay. Two or three MelanoDerm™ tissues were rinsed with CMF-DPBS, blotted dry on sterile absorbent paper and cleared of excess liquid. The MelanoDerm™ tissues were removed from the cell culture insert using sterile scalpels, placed in a labeled 1.5 mL microfuge tube, and stored at &lt;−60° C. for subsequent melanin analysis. 
     At least 16 hours after initiating the cultures, the rest of the tissues were transferred on a new 6-well plate containing 0.9 mL/well of fresh, pre-warmed EPI-100-LLMM. The trial was conducted over a 7-day timeframe. Four or five tissues were treated topically on the first day, and every 48 hours (within a timeframe of 48+2 hours from previous treatment) with 25 μL, of each test article. The medium was refreshed daily (within a timeframe of 24+2 hours from previous refeeding); the tissues were transferred to a new 6-well plate containing 0.9 mL/well of fresh, pre-warmed EPI-100-LLMM. 
     Four or five tissues were treated topically on the first day, and every 48 hours (within a timeframe of 48+2 hours from previous treatment) with 25 μL of positive and negative/solvent controls, respectively. The medium was refreshed daily (within a timeframe of 24+2 hours from previous refeeding); the tissues were transferred to a new 6-well plate containing 0.9 mL/well of fresh, pre-warmed EPI-100-LLMM. The tissues were incubated at 37±1° C. in a humidified atmosphere of 5±1% CO2 in air (standard culture conditions) for the appropriate exposure times. 
     On the days of dosing, the MelanoDerm™ tissue was first gently rinsed three times using ˜500 μL of CMF-DPBS per rinse to remove any residual test article. The CMF-DPBS was gently pipetted into the well and then drawn off with a sterile aspirator. The tissues were transferred to a new 6-well plate containing 0.9 mL of fresh, pre-warmed EPI-100-LLMM and dosed with the appropriate test article, negative/solvent or positive control. The tissues were incubated at 37±1° C. in a humidified atmosphere of 5±1% CO 2  in air (standard culture conditions) for the appropriate exposure times. 
     At the end of the 7-day trial, the MelanoDerm™ tissues treated with the negative/solvent or positive control, and with each test article were photographed using a digital camera to aid in the visual assessment of the degree of pigmentation of the tissues at the end of the assay (Day 7). Then, the viability of two tissues treated with the positive and negative control, respectively, and with each test article, were determined by MTT reduction. At the end of the 7-day trial, the melanin produced by three tissues treated with each test article, the positive and negative/solvent control, respectively, was determined. 
     MTT Assay: A 10× stock of MTT prepared in PBS (filtered at time of batch preparation) was thawed and diluted in warm MTT Addition Medium to produce the 1.0 mg/mL solution no more than two hours before use. Three hundred μL of the MTT solution was added to each designated well of a prelabelled 24-well plate. 
     After the exposure time, each MelanoDerm™ tissue designated for the MTT assay was rinsed with CMF-DPBS (use of spray bottle acceptable for this step), blotted dry on sterile absorbent paper, and cleared of excess liquid. The MelanoDerm™ tissues were transferred to the appropriate MTT containing wells after rinsing. The 24-well plates were incubated at standard conditions for 3±0.1 hours. 
     After 3±0.1 hours, the MelanoDerm™ tissues were blotted on sterile absorbent paper, cleared of excess liquid, and transferred to a prelabelled 24-well plate containing 2.0 mL of isopropanol in each designated well. The plates were covered with parafilm and stored in the refrigerator (2-8° C.) until the last exposure time was harvested. If necessary, plates were stored overnight (or up to 24 hours after the last exposure time is harvested) in the refrigerator prior to extracting the MTT. Then the plates were shaken for at least 2 hours at room temperature. At the end of the extraction period, the liquid within the cell culture inserts was decanted into the well from which the cell culture insert was taken. The extract solution was mixed and 200 μL transferred to the appropriate wells of 96-well plate. Two hundred μL of isopropanol was added to the wells designated as blanks. The absorbance at 550 nm (OD550) of each well was measured with a Molecular Devices Vmax plate reader. 
     Melanin Assay: At the end of the appropriate exposure times, the MelanoDerm™ tissues designated for the melanin assay were gently rinsed at least three times using ˜500 μL of CMF-DPBS per rinse to remove any residual test article or excess phenol red from culture medium, blotted dry on sterile absorbent paper and cleared of excess liquid. The MelanoDerm™ tissues were photographed using a digital camera at the end of the assay. The MelanoDerm™ tissues were removed from the cell culture insert using sterile scalpels or sterile punche(s), placed in a labeled 1.5 mL microfuge tube, and stored at &lt;−60° C. for subsequent melanin analysis. 
     On the day of the melanin extraction assay, the excised tissues were thawed at room temperature for approximately 10 minutes. 250 μL Solvable was added to each microfuge tube and the tubes were incubated for at least 16 hours at 60+2° C. A 1 mg/mL Melanin standard stock solution was prepared by dissolving the Melanin in Solvable. A series of Melanin standards was prepared from the 1 mg/mL stock ranging from 0 mg/mL to 0.33 mg/mL. The standard series was prepared by adding 0.6 mL of the 1 mg/mL Melanin standard stock solution to 1.2 mL Solvable, and then making a series of five more dilutions (dilution factor of 3). Solvable was used as the zero standard. The Melanin standards series and the Solvable were incubated for at least 16 hours at 60+2° C. 
     At least 16 hours after initiating the melanin extraction, the tubes containing the samples (representing the melanin extracted from the MelanoDerm™ tissues) and the standards were cooled at room temperature and centrifuged at 13,000 rpm for 5 minutes at room temperature. 200 μL of samples (single wells) or standards (duplicate wells) were transferred to the appropriate wells of a 96-well plate. Two hundred μL of Solvable were added to the wells designated as blanks in duplicate wells. The absorbance at 490 nm (OD490) of each well was measured with a Molecular Devices Vmax plate reader (with Automix function selected). 
     Killed Controls for Assessment of Residual Test Article Reduction of MTT 
     To demonstrate that possible residual test article was not acting to directly reduce the MTT, a functional check was performed in the definitive assay to show that the test material was not binding to the tissue and leading to a false MTT reduction signal. 
     To determine whether residual test article was acting to directly reduce the MTT, a freeze-killed control tissue was used. Freeze killed tissue was prepared by placing untreated MelanoDerm™/EpiDerm™ (Melanoderm™ without melanocytes) tissues in the −20° C. freezer at least overnight, thawing to room temperature, and then refreezing. Once killed, the tissue may be stored indefinitely in the freezer. Freeze killed tissues may be received already prepared from MatTek Corporation, and stored in the −20° C. freezer until use. To test for residual test article reduction, killed tissues were treated with the test article in the normal fashion. All assay procedures were performed in the same manner as for the viable tissue. At least one killed control treated with sterile deionized water (negative killed control) was tested in parallel since a small amount of MTT reduction is expected from the residual NADH and associated enzymes within the killed tissue. 
     If little or no MTT reduction was observed in the test article-treated killed control, the MTT reduction observed in the test article-treated viable tissue may be ascribed to the viable cells. If there was appreciable MTT reduction in the treated killed control (relative to the amount in the treated viable tissue), additional steps must be taken to account for the chemical reduction or the test article may be considered untestable in this system. 
     Data Analysis 
     The mean OD550 value of the blank wells was calculated. The corrected mean OD550 value of the negative/solvent control(s) was determined by subtracting the mean OD550 value of the blank wells from their mean OD550 values. The corrected OD550 values of the individual test article exposures and the positive control exposures was determined by subtracting from each the mean OD550 value for the blank wells. All calculations were performed using an Excel spreadsheet. Although the algorithms discussed are performed to calculate the final endpoint analysis at the treatment group level, the same calculations can be applied to the individual replicates. 
       Corr. Test article exposure OD 550 =Test article exposure OD 550 −Blank mean OD 550  
 
     If killed controls (KC) were used, the following additional calculations were performed to correct for the amount of MTT reduced directly by test article residues. The raw OD550 value for the negative control killed control was subtracted from the raw OD550 values for each of the test article-treated killed controls, to determine the net OD550 values of the test article-treated killed controls. 
       Net OD 550  for each test article KC=Raw OD 550  test article KC −Raw OD 550  negative/solvent control KC
 
     The net OD550 values represent the amount of reduced MTT due to direct reduction by test article residues at specific exposure times. In general, if the net OD550 value is greater than 0.150, the net amount of MTT reduction will be subtracted from the corrected OD550 values of the viable treated tissues to obtain a final corrected OD550 value. These final corrected OD550 values will then be used to determine the % of Control viabilities. 
       Final Corrected OD 550 =Corrected test article OD 550 (viable)−Net OD 550  test article (KC)
 
     Finally, the following % of Control calculations will be made: 
       % Viability=[(Final corrected OD 550  of Test Article or Positive Control)/(Corrected mean OD 550  of Negative/Solvent Control(s))]×100
 
     Melanin Analysis: The raw absorbance data was captured, saved as a print-file and imported into an Excel spreadsheet. The OD490 value of each test sample (representing the melanin extracted from untreated MelanoDerm™ tissues at Day 0, MelanoDerm™ tissues treated with each test article, negative/solvent or positive controls at Day 7) and of the melanin standards was determined. The corrected OD490 value for the test samples and each melanin standard was determined by subtracting the mean OD490 value of the blank wells. The standard curve was plotted as the concentration of the standards in mg/mL (y-axis) versus the corresponding corrected absorbance. The amount of melanin in each individual tissue was interpolated from the standard curve (linear). Finally, the average of melanin concentration for each test article or control treatment groups, respectively, was calculated. 
     Results 
       FIG. 1  summarizes the mean tissue viability and melanin concentration results for the test articles, positive control, and untreated tissues. Preliminary results suggest that certain formulations applied to the carbazole compounds of the present invention may independently exhibit moderate skin brightening effects that dampen the skin darkening activity of the carbazoles. 
       FIG. 2  summarizes the mean tissue viability and melanin concentration results for the test articles and untreated tissues observed in a separate experiment. Combination treatments comprising, for example, malassezin and indirubin, exhibited more effective skin brightening effects than either compound on its own. 
       FIG. 4  summarizes the mean tissue viability and melanin concentration results for the test articles, test compositions, positive control, and solvent control. The compounds comprising compositions #1 and #2 demonstrated synergistic effects when combined in a single composition. 
       FIG. 5  summarizes the mean tissue viability and melanin concentration results for the test articles, test compositions, positive control, and solvent control. The compounds comprising compositions #2, #3, #4, and #5 demonstrated synergistic effects when combined in a single composition. 
     Example 6 
     Melanogenesis Potential of Compositions Containing  Malassezia —Derived Compounds and/or Chemical Analogs Thereof 
     The purpose of this study is to observe and report melanogenesis and viability of B16 melanocytes exposed to compositions containing  Malassezia -derived compounds and/or chemical analogs thereof. 
     Materials and Reagents 
     Plating media will include DMEM without L-glutamine, FBS, penicillin/streptomycin, and L-glutamine. Assay media will include DMEM without phenol red and L-glutamine, FBS, penicillin/streptomycin, L-glutamine, and aMSH. Other reagents will include Kojic Acid, DMSO, and MTT. Cells tested will be B16 cells (ATCC CRL-6475). 
     Protocol 
     B16 Melanocytes are cultured until 70% confluent and harvested. Cells are seeded in 96-well plates at a density of 4000 cells/well and are allowed to attach overnight. The following day, test articles, test compositions, and controls are diluted in B16 Assay media. Overnight media is aspirated and 200 ul of test articles and controls are applied. Cells are incubated at 37° C. and 10% CO 2  for 72 hours. Following 72-hour incubation, absorbance is read at 540 nm. Media is removed and replaced with 100 ul of plating media containing 1 mg/mL MTT and incubated for 2 hours at 37° C. and 10% CO 2 . MTT media is removed and replaced with 200 ul of 95% Ethanol/5% Isopropanol and allowed to shake for 15 minutes. MTT absorbance then is read at 570 nm. 
     Results 
     It is expected that the compounds and compositions of the present invention, including Compositions #1-5, will inhibit melanogenesis. Compositions of the present invention are expected to exhibit, for example, more potent melanogenesis-inhibiting activity compared to at least one component compound. Likewise, certain compositions are expected to demonstrate, for example, less effective melanogenesis-inhibiting activity compared to at least one component compound. 
     Example 7 
     In Vitro Efficacy 
     It is expected that the compounds and compositions of the present invention will induce melanocyte apoptosis and modulate melanocyte activity, melanin production, melanin concentration, melanosome biogenesis, and/or melanosome transfer. It is also contemplated that certain of the compounds and compositions of the present invention will affect these biological processes less potently. Such compounds and compositions may have more favorable toxicity profiles compared to more potent species. 
     Example 8 
     In Vivo Efficacy 
     It is expected that the compounds and compositions of the present invention will modulate skin pigmentation, including brightening skin, and improving hyperpigmentation/hypopigmentation caused by various disorders. It is further expected that the compounds and compositions of the present invention will exhibit favorable pharmacokinetic profiles in terms of, for example, half-life and absorption. Certain compounds will exhibit a longer half-life, whereas others will exhibit a shorter half-life. Similarly, certain compounds will exhibit different absorption profiles, with some compounds taking longer to be fully absorbed and others taking less time to be fully absorbed. 
     Example 9 
     Synthesis of Chemical Analogs of Malassezin and Indirubin 
     Synthesis of AB17590 
     As shown in  FIG. 6A , to a solution of compound 1a (25.0 g, 0.357 mol, 1.0 eq) in tetrahydrofuran (250 mL) was added ethynylmagnesium bromide (0.5 M in THF, 1.07 L, 0.535 mol, 1.5 eq) at 0° C. and the reaction mixture was warmed to room temperature and stirred for 2 h. Then the mixture was quenched with saturated aqueous of ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous Na 2 SO 4  and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% ethyl acetate in petroleum ether) to give compound 1b (9.5 g, 27%). TLC: PE:EA=20:1, 254 nm; R f  (Compound 1a)=0.3; R f  (Compound 1b)=0.7. 
     To a mixture of compound 1b (9.5 g, 98.96 mmol, 1.0 eq) in tetrahydrofuran (100 mL) was added a solution of 60% sodium hydride (4.7 g, 0.119 mol, 1.2 eq) in dimethylformamide (50 mL) at 0° C. under nitrogen atmosphere. After 30 minutes, dimethyl sulphate (22.4 g, 0.178 mol, 1.8 eq) was added at 0° C. After the addition the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 30 min and then acetic acid (1 ml) was added slowly. The product was distilled directly from the reaction mixture. There was thus obtained compound 1c (10.0 g, 91% yield). 
     To a solution of compound 1 (8.0 g, 24.02 mmol, 1.0 eq) and compound 1c (2.9 g, 26.43 mmol, 1.1 eq) in triethylamine (80 mL) was added cuprous iodide (456 mg, 2.40 mmol, 0.1 eq) and Pd(PPh 3 ) 2 Cl 2  (337 mg, 0.480 mmol, 0.02 eq) at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for 2 h. The progress of the reaction mixture was monitored by TLC. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% ethyl acetate in petroleum ether) to give compound 2 (7.0 g, 92%). TLC: PE:EA=10:1, 254 nm; R f  (compound 1)=0.8; R f  (compound 2)=0.6. 
     To an oven-dried flask was added a mixture of platinum dichloride (694 mg, 2.06 mmol, 0.1 eq), sodium carbonate (3.3 g, 30.95 mmol, 1.5 eq), tris (pentafluorophenyl) phosphine (2.2 g, 4.13 mmol, 0.2 eq), 6-methyl indole (4.8 g, 41.27 mmol, 2.0 eq) and compound 2 (6.5 g, 20.63 mmol, 1.0 eq) in dioxane (650 mL). The flask was degassed with nitrogen, sealed and heated to 100° C. for 16 h. The progress of the reaction mixture was monitored by TLC. The solvent was concentrated under reduced pressure. The residue was diluted with ethyl acetate and extracted with water, saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% ethyl acetate in petroleum ether) to give compound 3 (3.0 g, 36%). TLC: PE:EA=10:1, 254 nm; R f  (compound 2)=0.6; R f  (compound 3)=0.2. 
     To a solution of compound 3 (3.0 g, 7.50 mmol, 1.0 eq) in tetrahydrofuran (30 mL) was added sodium methanolate (5 M in MeOH, 6.0 mL, 29.98 mmol, 4.0 eq) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The progress of the reaction mixture was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% ethyl acetate in petroleum ether) to give compound 4 (1.5 g, 66%). TLC: PE:EA=5:1, 254 nm; R f  (compound 3)=0.7; R f  (compound 4)=0.4. 
     To a dried 500 mL three-neck round-bottom flask under argon at 0° C., dimethylformamide (10 mL) was added. Then phosphorus oxychloride (1.2 g, 7.60 mmol, 1.2 eq) was slowly added while maintaining the internal temperature below 5C over 10 min. After stirring at 0° C. for 30 min, a solution of compound 4 (1.9 g, 6.33 mmol, 1.0 eq) in dimethylformamide (20 mL) was slowly added while maintaining the internal temperature below 5C over 10 min. The resulting mixture was stirred at room temperature for 16 h. After the reaction was complete (monitored by TLC using 20% ethyl acetate in hexanes), the reaction mixture was poured into saturated aqueous sodium bicarbonate (50 mL) and stirred for 1 h. Resulting mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, saturated brine and dried over sodium sulfate. The solvent was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-50% ethyl acetate in petroleum ether) to obtain compound 5 (1.8 g, 89%). TLC: PE:EA=1:1, 254 nm; R f  (compound 4)=0.8; R f  (compound 5)=0.5. 
     To a solution of compound 5 (1.8 g, 5.49 mmol, 1.0 eq) in tetrahydrofuran (20 mL) was added Di-tert-butyl dicarbonate (3.0 g, 13.72 mmol, 2.5 eq) and 4-Dimethylaminopyridine (1.4 g, 11.25 mol, 2.05 eq) at 0° C. The reaction mixture was warmed to room temperature and stirred for 3 h. The progress of the reaction mixture was monitored by TLC. The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate and washed with IN hydrochloric acid, saturated aqueous sodium bicarbonate (300 mL) and brine (300 mL). The organic layers were separated and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% ethyl acetate in petroleum ether) to obtain compound 6 (2.4 g, 82%). TLC: PE:EA=10:1, 254 nm; R f  (compound 5)=0.1; R f  (compound 6)=0.5. 
     To a solution of compound 6 (2.4 g, 4.55 mmol, 1.0 eq) in tert-Butanol (60 mL) was added 2-methyl-2-butene (30 mL) followed by addition of sodium chlorite (8.2 g, 90.91 mmol, 20.0 eq), sodium phosphate monobasic (14.2 g, 90.91 mmol, 20.0 eq) and water (60 mL) at 0° C. The mixture was slowly warmed to room temperature and stirred at room temperature for 15 h. The progress of the reaction mixture was monitored by TLC. The reaction mixture was diluted with dichloromethane (100 mL) and separated. The organic layer was washed with water (80 mL), brine (80 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude compound 7 (2.5 g, 99%). TLC: PE:EA=2:1, 254 nm; R f  (compound 6)=0.7; R f  (compound 7)=0.3. 
     To a solution of compound 7 (2.5 g, 4.60 mmol, 1.0 eq) in dimethylformamide (30 mL) was added potassium carbonate (952 mg, 6.89 mmol, 1.5 eq) and methyl iodide (978 mg, 6.89 mmol, 1.5 eq) at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 h. The progress of the reaction mixture was monitored by TLC. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5-17% ethyl acetate in petroleum ether) to obtain compound 8 (2.3 g, 89%). TLC: PE:EA=5:1, 254 nm; R f  (compound 7)=0.1; R f  (compound 8)=0.6. 
     A mixture of compound 8 (1.3 g, 2.33 mmol, 1.0 eq) in hydrochloric acid (3 M in EA, 30 mL) was stirred at room temperature for 16 h. The reaction was monitored by TLC. Then the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-25% ethyl acetate in petroleum ether) to give compound AB17590 (502 mg, 61%) as a yellow solid. TLC: PE:EA=3:1, 254 nm; R f  (compound 8)=0.8; R f  (compound AB17590)=0.5; LC-MS: 359 (M+1) + ;  1 H NMR (400 MHz, CDCl 3 ) δ 8.12 (d, J=19.7 Hz, 2H), 7.94 (s, 1H), 7.42 (s, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.13 (t, J=7.8 Hz, 1H), 7.04 (d, J=8.2 Hz, 1H), 6.93 (dd, J=15.7, 8.6 Hz, 2H), 5.04 (d, J=9.1 Hz, 1H), 3.95 (s, 3H), 2.45 (s, 3H), 1.42 (d, J=8.4 Hz, 1H), 0.78-0.68 (m, 1H), 0.62 (d, J=4.8 Hz, 1H), 0.54-0.41 (m, 2H). 
     Synthesis of AB17653 
     As shown in  FIG. 6B , a mixture of compound 1 (721 mg, 3.20 mmol, 1.0 eq), compound 1a (560 mg, 3.20 mmol, 1.0 eq) and sodium carbonate (866 mg, 8.17 mmol, 2.55 eq) in methanol (10 mL) was stirred at room temperature for 3 h under nitrogen atmosphere. The progress of the reaction mixture was monitored by TLC. After completion of the reaction, the mixture was filtered and the filter cake was washed with methanol and water to afford compound AB17653 (979 mg, 89%) as a red solid. TLC: PE/EA=3/1, 254 nm; R f  (Compound 1)=0.6; R f  (Compound AB17653)=0.4; LC-MS: 338.95 (M−1) − ;  1 H NMR (400 MHz, d6-DMSO) δ 11.01 (d, J=21.5 Hz, 2H), 8.64 (d, J=8.3 Hz, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.55 (t, J=7.6 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.00 (dd, J=8.8, 4.6 Hz, 2H). 
     Synthesis of AB17654 
     As shown in  FIG. 6B , a mixture of compound AB17653 (979 mg, 2.88 mmol, 1.0 eq) and hydroxylamine hydrochloride (520 mg, 7.49 mmol, 2.6 eq) in pyridine (30 mL) was stirred at 120° C. for 2 h under nitrogen atmosphere. The progress of the reaction mixture was monitored by LCMS. After completion of the reaction, the mixture was concentrated under reduced pressure and added 1 N HCl until the solid appeared. The mixture was filtered and the filter cake was dissolved in 1 N NaOH. Then 3 N HCl was added to adjust pH=5 and filtered. The filter cake was washed with 1 N HCl to afford compound AB17654 (500 mg, 48%) as a red solid. LC-MS: 357.95 (M+1) + ;  1 H NMR (400 MHz, d6-DMSO) 13.59 (s, 1H), 11.71 (s, 1H), 10.82 (s, 1H), 8.53 (d, J=8.4 Hz, 1H), 8.19 (d, J=7.7 Hz, 1H), 7.42-7.35 (m, 2H), 7.11-6.96 (m, 3H). 
     Synthesis of AB17655 
     As shown in  FIG. 6B , a mixture of compound 2 (637 mg, 3.86 mmol, 1.0 eq), compound 1a (676 mg, 3.86 mmol, 1.0 eq) and sodium carbonate (1044 mg, 9.84 mmol, 2.55 eq) in methanol (10 mL) was stirred at room temperature for 3 h under nitrogen atmosphere. The progress of the reaction mixture was monitored by TLC. After completion of the reaction, the mixture was filtered and the filter cake was washed with methanol and water to afford compound AB17655 (1027 mg, 95%) as a red solid. LC-MS: 281.05 (M+1) + ;  1 H NMR (400 MHz, d6-DMSO) δ 11.06 (s, 1H), 10.86 (s, 1H), 8.54 (dd, J=10.5, 2.7 Hz, 1H), 7.67-7.53 (m, 2H), 7.41-7.38 (m, 1H), 7.09-6.98 (m, 2H), 6.85 (dd, J=8.5, 4.8 Hz, 1H). 
     Synthesis of AB17656 
     As shown in  FIG. 6B , a mixture of compound AB17655 (1027 mg, 3.67 mmol, 1.0 eq) and hydroxylamine hydrochloride (663 mg, 9.54 mmol, 2.6 eq) in pyridine (30 mL) was stirred at 110° C. for 2 h under nitrogen atmosphere. The progress of the reaction mixture was monitored by LCMS. After completion of the reaction, the mixture was concentrated under reduced pressure and added 1 N HCl until the solid appeared. The mixture was filtered and the filter cake was dissolved in 1 N NaOH. Then 3 N HCl was added to adjust pH=5 and filtered. The filter cake was washed with 1 N HCl to afford compound AB17656 (500 mg, 48%) as a red solid. LC-MS: 296.00 (M+1) + ;  1 H NMR (400 MHz, d6-DMSO) δ 13.60 (s, 1H), 11.77 (s, 1H), 10.69 (s, 1H), 8.43 (s, 1H), 8.20 (d, J=7.7 Hz, 1H), 7.39 (d, J=5.7 Hz, 2H), 7.02 (s, 1H), 6.91 (s, 1H), 6.83 (d, J=4.9 Hz, 1H). 
     Synthesis of AB17657 
     As shown in  FIG. 6B , a mixture of compound 3 (362 mg, 2.46 mmol, 1.0 eq), compound 1a (431 mg, 2.46 mmol, 1.0 eq) and sodium carbonate (666 mg, 6.28 mmol, 2.55 eq) in methanol (10 mL) was stirred at room temperature for 3 h under nitrogen atmosphere. The progress of the reaction mixture was monitored by TLC. After completion of the reaction, the mixture was filtered and the filter cake was washed with methanol and water to afford compound 4 (606 mg, 93%). TLC: PE/EA=1/1, 254 nm; R f  (Compound 3)=0.7; R f  (Compound 4)=0.5. 
     A mixture of compound 4 (606 mg, 2.31 mmol, 1.0 eq) and hydroxylamine hydrochloride (418 mg, 6.01 mmol, 2.6 eq) in pyridine (20 mL) was stirred at 120° C. for 2 h under nitrogen atmosphere. The progress of the reaction mixture was monitored by TLC. After completion of the reaction, the mixture was concentrated under reduced pressure and added 1 N HCl until the solid appeared. The mixture was filtered and the filter cake was dissolved in 1 N NaOH. Then 3 N HCl was added to adjust pH=5 and filtered. The filter cake was washed with 1 N HCl to afford compound AB17657 (500 mg, 78%) as a brown solid. TLC: PE/EA=1/1, 254 nm; R f  (Compound 4)=0.5; R f  (Compound AB17657)=0.4; LC-MS: 278.10 (M+1) + ;  1 H NMR (400 MHz, d6-DMSO) δ 13.60 (s, 1H), 11.77 (s, 1H), 10.69 (s, 1H), 8.43 (s, 1H), 8.20 (d, J=7.7 Hz, 1H), 7.39 (d, J=5.7 Hz, 2H), 7.02 (s, 1H), 6.91 (s, 1H), 6.83 (d, J=4.9 Hz, 1H). 
     Synthesis of AB17658 
     As shown in  FIG. 6B , a mixture of compound 5a (337 mg, 1.73 mmol, 1.0 eq), compound 5b (554 mg, 1.73 mmol, 1.0 eq) and potassium hydroxide (1114 mg, 3.46 mmol, 2.0 eq) in acetonitrile (10 mL) was stirred at 35° C. for 1.5 h under nitrogen atmosphere. The progress of the reaction mixture was monitored by TLC. After completion of the reaction, the mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography to afford compound 5c (436 mg, 99%). TLC: PE/EA=1/1, 254 nm; R f  (Compound 5a)=0.8; R f  (Compound 5c)=0.5. 
     A mixture of compound 5 (330 mg, 1.72 mmol, 1.0 eq), compound 5c (436 mg, 1.72 mmol, 1.0 eq) and sodium carbonate (465 mg, 4.38 mmol, 2.55 eq) in methanol (10 mL) was stirred at room temperature for 3 h under nitrogen atmosphere. The progress of the reaction mixture was monitored by TLC. After completion of the reaction, the mixture was filtered and the filter cake was washed with methanol and water to afford compound 6 (617 mg, 93%). TLC: PE/EA=1/1, 254 nm; R f  (Compound 5)=0.5; R f  (Compound 6)=0.4. 
     A mixture of compound 6 (617 mg, 1.60 mmol, 1.0 eq) and hydroxylamine hydrochloride (290 mg, 4.17 mmol, 2.6 eq) in pyridine (20 mL) was stirred at 110° C. for 2 h under nitrogen atmosphere. The progress of the reaction mixture was monitored by TLC. After completion of the reaction, the mixture was concentrated under reduced pressure and added 1 N HCl until the solid appeared. The mixture was filtered and the filter cake was dissolved in 1 N NaOH. Then 3 N HCl was added to adjust pH=5 and filtered. The filter cake was washed with 1 N HCl to afford compound AB17658 (500 mg, 78%) as a red solid. TLC: PE/EA=1/1, 254 nm; R f  (Compound 6)=0.4; R f  (Compound AB17658)=0.3; LC-MS: 402.95 (M+1) + ;  1 H NMR (400 MHz, d6-DMSO) δ 11.86 (s, 1H), 11.39 (s, 1H), 9.40 (d, J=2.2 Hz, 1H), 8.33 (d, J=1.8 Hz, 1H), 8.06 (dd, J=8.6, 2.4 Hz, 1H), 7.59 (dd, J=8.4, 2.0 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H). 
     Example 10 
     In Vivo Assessment of the Photoprotective Properties of Malassezin, Other  Malassezia —Derived Compounds, and Chemical Analogs Thereof 
     Malassezin 1% Formulation 
     The Malassezin 1% formulation used in this study contained the following ingredients: Water (aqua)—65.939%; Dimethyl isosorbide—20.000%; Olive Oil Glycereth-8 Esters—3.000%; Glycerin—2.991%; Coconut Alkanes—2.700%; Hydroxyethyl Acrylate/Sodium Acryloyldimethyl Taurate Copolymer—1.700%; Malassezin—1.000%; Pentylene Glycol—1.000%; Phenoxyethanol—0.640%; Coco-Caprylate/Caprate—0.300%; Caprylyl Glycol—0.200%; Chlorphenesin—0.160%; Sorbitan Isostearate—0.140%; Tocopherol—0.100%; Polysorbate 60-0.080%; and Disodium EDTA—0.050%. 
     Experimental Design 
     A 39-year-old Skin Type IV female was included in this Proof of Concept study. 
     On Day 1 of the experiment, the subject was evaluated to determine Minimal Erythema Dosing (“MED”) using a targeted broad band Dualight UVB device. A template of 6 squares was placed on the lower left back (1.5 cm×1.5 cm) of the test subject. See  FIG. 7 . 
     The MED photo test doses for the subject&#39;s skin type are listed in  FIG. 8  in mJ/cm 2  units. Twenty-four hours after irradiation, the subject returned for MED assessment. As shown in  FIG. 12 , the subject&#39;s MED was 120 mJ. 
     Subsequently, the subject applied Malassezin 1% in the superior test square of the right back twice daily for 7 days. A second right lower square was treated twice daily from day 4 to day 7, and a third medial square for one application on day 7. The product vehicle was applied for 7 days twice daily on the left back. See  FIG. 13 . The subject returned to the research center for irradiation on day 7. Each test site was irradiated with 120 mJ of UVB exposure. The subject returned in 24 hours for assessment of phototoxicity/photoprotection. See  FIG. 14 . 
     The subject continued the experiment, receiving Malassezin 1% for a total of 14 days.  FIGS. 15-16  show regions of the subject&#39;s skin exposed to the following treatments: on site 14, Malassezin 1% was applied twice a day for 14 days; on site 10, Malassezin 1% was applied twice a day for 11 days; on site 8, Malassezin 1% was applied twice a day for 8 days; on site 3, Malassezin 1% was applied twice a day for 3 days; on site 1, Malassezin 1% was applied once; and, on the vehicle sites, vehicle was applied twice a day for 7 and 9 days, respectively. 
     Results 
     As shown in  FIG. 14 , 24 hours after UVB exposure, the subject exhibited 1 plus to 2 plus erythema at the vehicle test site. See  FIG. 11  for erythema scale. In contrast, there was less erythema (mild) noted at the Malassezin 1% 7-day treatment site. Evaluation of sites treated for 3 days showed minimal erythema and none for the 1-day application site. Colorimetry measurements were taken from each site using the Mexameter MX16 and supported clinical observations. Maximal erythema readings were observed in the vehicle site followed by the Malassezin 7-day-treated site. The lowest values were observed for the Malassezin day 3 and day 1 site, respectively. See  FIG. 9 . 
     The subject continued the experiment and returned for a repeat UVB irradiation at 14 days with interpretation at day 15. See  FIG. 15 . Clinical evaluation at day 15 revealed moderate erythema at the vehicle site for day 7 and significantly less at day 9. See  FIG. 16 . Less erythema (mild) was noted at the Malassezin 1%-treated sites, including the day 14, day 10, and day 8 sites. Minimal erythema was noted at Malassezin 1% sites for days 1 and day 3. Colorimetry readings were taken from each site to measure erythema and the melanin index. Results supported clinical observations of less erythema at the Malassezin 1%-treated sites. See  FIG. 10 . 
     Biopsies were taken from the vehicle site at 9 days and the Malassezin 1%-treated sites for days 1 and 3. Specimens were analyzed for Hematoxylin and Eosin, Fontana Masson staining and MART I for quantification of melanocytes and affymetrix studies. The following qualitative evaluations were made: 
     Diagnosis: (A) Skin—Day 1 Treated (Malassezin 1%): Basket weave stratum corneum, normal appearing melanocytes (confirmed by immunoperoxidase staining with Mart-1), and epidermal melanin (confirmed by immunoperoxidase staining with Fontana Masson). 
     Diagnosis: (B) Skin—Day 3 Treated (Malassezin 1%): Basket weave stratum corneum, less dendritic melanocytes (confirmed by immunoperoxidase staining with MART-1/Melan A) when compared to C and D, and with a slight decrease in epidermal melanin, as skip areas (confirmed by immunoperoxidase staining with Fontana Masson). 
     Diagnosis: (C) Skin—Vehicle: Normal appearing epidermal melanocytes (confirmed by immunoperoxidase staining with Mart-1) and epidermal melanin (confirmed by immunoperoxidase staining with Fontana Masson). 
     Diagnosis: (D) Skin—Normal: Normal appearing epidermal melanocytes (confirmed by immunoperoxidase staining with Mart-1) and epidermal melanin (confirmed by immunoperoxidase staining with Fontana Masson). 
     Conclusions 
     The results of this Proof of Concept study demonstrate the UV-protective properties of Malassezin. 
     Example 11 
     Assessment of the Effect of Malassezin on Fine Lines and Wrinkles by Gene Expression Analysis 
     Malassezin&#39;s effects on the expression of enzymes involved in procollagen formation and elastin breakdown were investigated. Genes involved with increase of collagen and decrease of elastin breakdown were significantly changed after treatment of human subjects with test compounds as detailed below. 
     Collagen is a protein that functions, in conjunction with elastin, to form the structural proteins of the extracellular matrix of the skin. Collagen is synthesized by fibroblasts as precursor molecules called procollagen. Procollagen is then secreted by the cell; outside the cell, it is formed into collagen fibrils. The synthesis of collagen is controlled by Transforming Growth Factor Beta (TGFbeta). Collagen is broken down in the skin by Matrix Metalloproteinases (MMPs). Elastin is formed in a similar manner to collagen from the precursor molecule tropoelastin. Elastin naturally decreases with age and is similarly broken down by MMPs. 
     Collagen levels can be decreased in two ways: inhibition of the formation of procollagen and degradation by matrix metalloproteinases (MMPs). Inhibition of formation of procollagen is accomplished by inhibition of TGFbeta. Environmental factors such as UV and oxidative stress can activate MMPs thereby increasing collagen degradation. A regulator of the collagen degradation pathway, Tissue Inhibitor of Metalloproteinases (TIMPs), inhibits MMPs, thereby decreasing collagen degradation. 
     Conversely, collagen can be increased in multiple ways through the skin. First, TGFbeta can be increased allowing for a larger quantity of procollagen to be synthesized. Second, MMPs can be inhibited through TIMPs allowing for a decrease in collagen breakdown. The situations do not need to occur together to increase collagen. However, if they do occur together, the increase in collagen is greater. The results are tabulated below. 
     Differential gene fold expression analysis was used to analyze Malassezin and compound AB17151. Biopsies from human subjects were taken after 6 weeks of application of compounds. Two participants applied AB17151 and one participant applied Malassezin. Biopsies were taken of treated skin and, as a control and for comparison, from untreated skin. The biopsies were assayed for change in RNA expression of the genes indicated in the table below. 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Effect of Malassezin on collagen formation and breakdown 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 treated 
                   
                   
               
               
                   
                   
                 with: 
               
               
                 gene 
                   
                 Malassezin: 
                 AB17151: 
                 AB17151: 
               
               
                 measured 
                   
                 PG 
                 CR 
                 ME 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 COL1A1 
                 Collagen, type 1, alpha 1 
                 (1.27) 
                 5.61 
                 (1.27) 
               
               
                 COL1A2 
                 Collagen, type 1, alpha 2 
                 (1.37) 
                 6.97 
                 1.99 
               
               
                 COL3A1 
                 Collagen, type III, alpha 1 
                 1.7 
                 6.26 
                 2.59 
               
               
                 COL5A1 
                 Collagen, type V, alpha 1 
                 (−1.15) 
                 6.1 
                 (1.41) 
               
               
                 COL5A2 
                 Collagen, type V, alpha 2 
                 (1.24) 
                 2.23 
                 (−1.03) 
               
               
                 PCOLCE2 
                 Pro-Collagen C endopeptidase 
                 2.93 
                 1.5 
                 1.57 
               
               
                   
                 enhancer 2 
               
               
                 MMP7 
                 Matrix Metalloproteinase 7 
                 −2.81 
                 (1.02) 
                 1.79 
               
               
                 MMP12 
                 Matrix Metalloproteinase 12 
                 (1.25) 
                 −21.44 
                 (−1.01) 
               
               
                   
               
            
           
         
       
     
     In the Table, numbers in parentheses indicate changes that are not statistically significant. All numbers indicate fold change in expression. Negative values indicate decreases in activity. A minus-3-fold change in activity, for example, means that the value changed by minus-3-fold, meaning it changed to ⅓ of its original value. 
     Malassezin induced an increase in Pro-collagen C Endopeptidase Enhancer 2 (PCOLCE2) which is involved in the formation of procollagen, the building block of collagen. Collagen genes were increased in both AB17151 samples, with some genes being changed up to 7-fold. One AB17151 sample also greatly decreased Matrix Metallopeptidase 12 (MMP12), which is involved in the breakdown of elastin. Malassezin inhibited Matrix Metallopeptidase 7 (MMP7), also involved in the breakdown of elastin. 
     These data indicate that Malassezin&#39;s effects on fine lines and wrinkles (discussed in the following example) may arise from Malassezin promoting procollagen formation, by enhancing the collagen/pro-collagen genes as indicated above and/or by inhibiting elastin breakdown by, for example, matrix metalloproteinase 7. 
     Example 12 
     In Vivo Assessment of the Effect of Malassezin on Fine Lines and Wrinkles 
     Malassezin formulations were evaluated for their effect on fine lines and wrinkles. In this study, human subjects with skin containing areas of hyperpigmentation were randomized to one of 3 groups. Product use groups included Malassezin 0.05%, 0.1%, and 1.0%. One mL of product (formulations detailed below) was applied to the face of subjects twice daily. Five minutes after the morning application, an SPF 50 sunscreen was applied to protect the treated areas from sun. Each subject had assessments at Baseline, 2, 4, 8, 14, 18 and 22 weeks. Treatment was ceased at 14 weeks. Week 18 and week 22 observations were to determine any return towards baseline. 
     Eleven subjects using the test ingredient completed week 14. The following analysis was compiled based on this data. An M.D. dermatologist with experience in evaluating fine lines and wrinkles performed evaluations on the subjects in this study and obtained the measurements tabulated below. Wrinkle assessment, classification, and evaluation were performed as described in G. Lemperle et al.,  A classification of facial wrinkles , Plast. Reconstr. Surg. 108: 1735 (2001), incorporated by reference herein in its entirety. The following data were obtained. For each subject, the percentage Malassezin formulation is indicated. 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 Fine lines/wrinkles data. 
               
            
           
           
               
               
               
               
               
               
            
               
                 Subject 
                 Week 0 
                 Week 2 
                 Week 4 
                 Week 8 
                 Week 14 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 VT01 (0.5%) 
                 3 
                 2 
                 2 
                 2 
                 2 
               
               
                 VT02 (0.1%) 
                 2 
                 3 
                 3 
                 3 
                 3 
               
               
                 VT03 (0.5%) 
                 3 
                 3 
                 3 
                 3 
                 3 
               
               
                 VT04 (1.0%) 
                 3 
                 3 
                 2 
                 2 
                 2 
               
               
                 VT05 (0.1%) 
                 2 
                 0 
                 0 
                 0 
                 0 
               
               
                 VT06 (0.5%) 
                 3 
                 2 
                 2 
                 2 
                 2 
               
               
                 VT07 (1.0%) 
                 3 
                 2 
                 2 
                 2 
                 2 
               
               
                 VT08 (0.1%) 
                 2 
                 1 
                 1 
                 1 
                 1 
               
               
                 VT09 (0.5%) 
                 2 
                 0 
                 0 
                 0 
                 0 
               
               
                 VT10 (1.0%) 
                 2 
                 1 
                 1 
                 1 
                 1 
               
               
                 VT11 (0.1%) 
                 3 
                 3 
                 3 
                 3 
                 3 
               
               
                 Average 
                 2.55 
                 1.82 
                 1.73 
                 1.73 
                 1.73 
               
               
                 P-value 
                   
                 0.024 
                 0.011 
                 0.011 
                 0.011 
               
               
                 (Student&#39;s T 
               
               
                 test) 
               
               
                   
               
            
           
         
       
     
     A subject self-assessment was completed at every visit. A total number of eleven (11) subjects were asked to respond to the questions regarding the improvement (if any) in their lines and wrinkles and related skin texture, tone, and firmness. Each answer was ranked from 6 to 1, with each having the meaning: 6—Strongly agree, 5—Agree, 4—Agree somewhat, 3—Disagree somewhat, 2—Disagree, and 1—Strongly disagree. The percentage of subjects answering with a score of 6 or 5 was calculated and is presented in the data below. 
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 Subject self-assessment. 
               
            
           
           
               
               
               
               
               
               
            
               
                 Number 
                 Question/Statement 
                 Week 2 
                 Week 4 
                 Week 8 
                 Week 14 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 1 
                 My Lines and wrinkles 
                 36.36% 
                 54.55% 
                 63.64% 
                 90.91% 
               
               
                   
                 are less visible 
               
               
                 2 
                 I have smoother skin 
                 45.45% 
                 63.64% 
                 81.82% 
                 90.91% 
               
               
                   
                 texture 
               
               
                 3 
                 My skin texture is less 
                 54.55% 
                 63.64% 
                 72.73% 
                 100.00% 
               
               
                   
                 coarse 
               
               
                 4 
                 My skin has a brighter 
                 45.45% 
                 63.64% 
                 72.73% 
                 81.82% 
               
               
                   
                 tone 
               
               
                 5 
                 My skin firmness has 
                 36.36% 
                 63.64% 
                 63.64% 
                 72.73% 
               
               
                   
                 improved 
               
               
                 6 
                 My skin looks more 
                 45.45% 
                 63.64% 
                 81.82% 
                 72.73% 
               
               
                   
                 youthful and healthy 
               
               
                 7 
                 Overall skin texture is 
                 54.55% 
                 63.64% 
                 81.82% 
                 90.91% 
               
               
                   
                 improved 
               
               
                 8 
                 Overall skin tone is 
                 54.55% 
                 63.64% 
                 72.73% 
                 81.82% 
               
               
                   
                 improved 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 Legend for preceding table. 
               
            
           
           
               
               
            
               
                   
                 Legend for Questionnaire Scoring 
               
               
                 Score 
                 Meaning 
               
               
                   
               
            
           
           
               
               
               
            
               
                 6 
                 Strongly Agree 
                 Top 2 Box 
               
               
                 5 
                 Agree 
               
               
                 4 
                 Somewhat Agree 
               
               
                 3 
                 Somewhat Disagree 
               
               
                 2 
                 Disagree 
               
               
                 1 
                 Strongly Disagree 
               
               
                   
               
            
           
         
       
     
     The following formulations were applied as described above and are examples of compositions of the invention: 
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 1% Malassezin formulation 
               
            
           
           
               
               
               
            
               
                 Ingredient 
                 Percentage 
                 Use 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Water (Aqua) 
                 65.94% 
                 Solvent 
               
               
                 Dimethyl Isosorbide 
                 20.00% 
                 Solvent, skin penetrant 
               
               
                 Olive Oil Glycereth-8 Esters 
                 3.00% 
                 Emulsifying agent, 
               
               
                   
                   
                 emmolient 
               
               
                 Glycerin 
                 2.99% 
                 Humectant, solvent 
               
               
                 Coconut Alkanes 
                 2.70% 
                 Emmolient, solvent 
               
               
                 Hydroxyethyl 
                 1.70% 
                 Emulsion stabilizer 
               
               
                 Aerylate/Sodium 
               
               
                 Acryloyldimethyl Taurate 
               
               
                 Copolymer 
               
               
                 Malassezin 
                 1.00% 
                 Ingredient under study; 
               
               
                   
                   
                 skin brightener 
               
               
                 Pentylene Glycol 
                 1.00% 
                 Skin penetrant 
               
               
                 Phenoxyethanol 
                 0.64% 
                 Preservative 
               
               
                 Coco-Caprylate/Caprate 
                 0.30% 
                 Emmolient 
               
               
                 Caprylyl Glycol 
                 0.20% 
                 Emmolient 
               
               
                 Chlorphenesin 
                 0.16% 
                 Preservative 
               
               
                 Sorbitan Isostearate 
                 0.14% 
                 Emulsifying agent 
               
               
                 Tocopherol 
                 0.10% 
                 Antioxidant 
               
               
                 Polysorbate 60 
                 0.08% 
                 Emulsifying agent 
               
               
                 Disodium EDTA 
                 0.05% 
                 Chelating agent 
               
               
                 Total: 
                 100.00% 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 0.5% Malassezin formulation 
               
            
           
           
               
               
               
            
               
                 Ingredient 
                 Percentage 
                 Use 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Water (Aqua) 
                 66.44% 
                 Solvent 
               
               
                 Dimethyl Isosorbide 
                 20.00% 
                 Solvent, skin penetrant 
               
               
                 Olive Oil Glycereth-8 Esters 
                 3.00% 
                 Emulsifying agent, 
               
               
                   
                   
                 emmolient 
               
               
                 Glycerin 
                 2.99% 
                 Humectant, solvent 
               
               
                 Coconut Alkanes 
                 2.70% 
                 Emmolient, solvent 
               
               
                 Hydroxyethyl Aerylate/Sodium 
                 1.70% 
                 Emulsion stabilizer 
               
               
                 Acryloyldimethyl Taurate 
               
               
                 Copolymer 
               
               
                 Pentylene Glycol 
                 1.00% 
                 Skin penetrant 
               
               
                 Phenoxyethanol 
                 0.64% 
                 Preservative 
               
               
                 Malassezin 
                 0.50% 
                 Ingredient under study; 
               
               
                   
                   
                 skin brightener 
               
               
                 Coco-Caprylate/Caprate 
                 0.30% 
                 Emmolient 
               
               
                 Caprylyl Glycol 
                 0.20% 
                 Emmolient 
               
               
                 Chlorphenesin 
                 0.16% 
                 Preservative 
               
               
                 Sorbitan Isostearate 
                 0.14% 
                 Emulsifying agent 
               
               
                 Tocopherol 
                 0.10% 
                 Antioxidant 
               
               
                 Polysorbate 60 
                 0.08% 
                 Emulsifying agent 
               
               
                 Disodium EDTA 
                 0.05% 
                 Chelating agent 
               
               
                 Total: 
                 100.00% 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                 0.1% Malassezin formulation 
               
            
           
           
               
               
               
            
               
                 Ingredient 
                 Percentage 
                 Use 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Water (Aqua) 
                 66.84% 
                 Solvent 
               
               
                 Dimethyl Isosorbide 
                 20.00% 
                 Solvent, skin penetrant 
               
               
                 Olive Oil Glycereth-8 Esters 
                 3.00% 
                 Emulsifying agent, 
               
               
                   
                   
                 emmolient 
               
               
                 Glycerin 
                 2.99% 
                 Humectant, solvent 
               
               
                 Coconut Alkanes 
                 2.70% 
                 Emmolient, solvent 
               
               
                 Hydroxyethyl Acrylate/Sodium 
                 1.70% 
                 Emulsion stabilizer 
               
               
                 Acryloyldimethyl Taurate 
               
               
                 Copolymer 
               
               
                 Pentylene Glycol 
                 1.00% 
                 Skin penetrant 
               
               
                 Phenoxyethanol 
                 0.64% 
                 Preservative 
               
               
                 Coco-Caprylate/Caprate 
                 0.30% 
                 Emmolient 
               
               
                 Caprylyl Glycol 
                 0.20% 
                 Emmolient 
               
               
                 Chlorphenesin 
                 0.16% 
                 Preservative 
               
               
                 Sorbitan Isostearate 
                 0.14% 
                 Emulsifying agent 
               
               
                 Malassezin 
                 0.10% 
                 Ingredient under study; 
               
               
                   
                   
                 skin brightener 
               
               
                 Tocopherol 
                 0.10% 
                 Antioxidant 
               
               
                 Polysorbate 60 
                 0.08% 
                 Emulsifying agent 
               
               
                 Disodium EDTA 
                 0.05% 
                 Chelating agent 
               
               
                   
                 100.00% 
               
               
                   
               
            
           
         
       
     
     Example 13 
     In Vivo Assessment of the Effect of Malassezin on Skin Brightening 
     In the study of the immediately preceding example, data relating to skin brightening was also collected from the treated subjects. Each subject had hyperpigmentation from either melasma or from post inflammatory hyper pigmentation. As used in the table below, “Inv”, an abbreviation of “involved”, refers to the area of the face that had hyperpigmentation. The “Uninv”, an abbreviation of “uninvolved”, refers to the area of the face that did not have hyperpigmented skin. Both Inv and Uninv areas were treated. 
     Evaluation: Colorimetry measurements using the Mexameter MX 18 were used at Baseline, and Weeks 2, 4, 8, 14, 18, and 22. Clinical assessments of depigmentation was performed in the treated area. Assessments were performed at Baseline, and Weeks 2, 4, 8, 14, 18, and 22. Brightening assessments included brightening of normal skin and/or severity of dyschromia, if present (see scale). Global improvement was measured at at the same time intervals. At all visits any adverse events (AE) was to be recorded including itching, burning, erythema, edema, dryness, scaling or skin peeling (see rating scales). No AEs were recorded. In the data reported below, negative percentages indicate reduced pigmentation, which indicates brightening. Positive percentages indicate increased pigmentation, which indicates darkening. “Conc.” indicates the concentration of Malassezin in the formulation administered to the subject. 
     
       
         
           
               
             
               
                 TABLE 15 
               
               
                   
               
               
                 Skin brightening data. 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Subject 
                 Conc. 
                 Diagnosis 
               
               
                   
                   
               
               
                   
                 VT01 
                 0.5% 
                 Photodamage 
               
               
                   
                 VT02 
                 0.1% 
                 Photodamage 
               
               
                   
                 VT03 
                 0.5% 
                 Photodamage 
               
               
                   
                 VT04 
                 1.0% 
                 Photodamage 
               
               
                   
                 VT05 
                 0.1% 
                 Photodamage 
               
               
                   
                 VT06 
                 0.5% 
                 Melasma 
               
               
                   
                 VT07 
                 1.0% 
                 Melasma 
               
               
                   
                 VT08 
                 0.1% 
                 Melasma 
               
               
                   
                 VT09 
                 0.5% 
                 Melasma 
               
               
                   
                 VT10 
                 1.0% 
                 Melasma 
               
               
                   
                 VT11 
                 0.1% 
                 Photodamage 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Week 0 
                 Week 2 
                 Week 4 
                 Week 8 
                 Week 14 
               
               
                 Subject 
                 Inv 
                 Inv 
                 Inv 
                 Inv 
                 Inv 
               
               
                   
               
               
                 VT01 
                 0.00% 
                 −1.35% 
                 −3.73% 
                 −7.76% 
                 −12.42% 
               
               
                 VT02 
                 0.00% 
                 −1.65% 
                 −1.75% 
                 −2.16% 
                 −2.37% 
               
               
                 VT03 
                 0.00% 
                 −3.64% 
                 −4.85% 
                 −5.83% 
                 −8.37% 
               
               
                 VT04 
                 0.00% 
                 −0.72% 
                 −1.30% 
                 −2.75% 
                 −5.51% 
               
               
                 VT05 
                 0.00% 
                 0.00% 
                 −0.17% 
                 −5.39% 
                 −7.65% 
               
               
                 VT06 
                 0.00% 
                 0.27% 
                 −0.99% 
                 −1.08% 
                 −7.48% 
               
               
                 VT07 
                 0.00% 
                 −0.61% 
                 −3.65% 
                 −4.82% 
                 −4.41% 
               
               
                 VT08 
                 0.00% 
                 0.33% 
                 −0.66% 
                 −3.70% 
                 −4.61% 
               
               
                 VT09 
                 0.00% 
                 0.17% 
                 −0.83% 
                 −0.99% 
                 −8.44% 
               
               
                 VT10 
                 0.00% 
                 −9.78% 
                 −16.44% 
                 −16.58% 
                 −18.48% 
               
               
                 VT11 
                 0.00% 
                 −6.73% 
                 −7.14% 
                 −7.96% 
                 −7.35% 
               
               
                 Average 
                 0.00% 
                 −3.71% 
                 −7.13% 
                 −8.05% 
                 −9.47% 
               
               
                 for 1.0% 
               
               
                 Average 
                 0.00% 
                 −1.14% 
                 −2.60% 
                 −3.92% 
                 −9.18% 
               
               
                 for 0.5% 
               
               
                 Average 
                 0.00% 
                 −2.01% 
                 −2.43% 
                 −4.80% 
                 −5.49% 
               
               
                 for 0.1% 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Week 0 
                 Week 2 
                 Week 4 
                 Week 8 
                 Week 14 
               
               
                 Subject 
                 Uninv 
                 Uninv 
                 Uninv 
                 Uninv 
                 Uninv 
               
               
                   
               
               
                 VT01 
                 0.00% 
                 −2.71% 
                 −5.65% 
                 −6.44% 
                 −8.93% 
               
               
                 VT02 
                 0.00% 
                 −3.91% 
                 −6.19% 
                 −7.82% 
                 −7.71% 
               
               
                 VT03 
                 0.00% 
                 3.12% 
                 1.22% 
                 0.00% 
                 −1.22% 
               
               
                 VT04 
                 0.00% 
                 −0.60% 
                 −3.19% 
                 −3.59% 
                 −7.37% 
               
               
                 VT05 
                 0.00% 
                 −0.45% 
                 −8.56% 
                 −8.78% 
                 −12.39% 
               
               
                 VT06 
                 0.00% 
                 −5.25% 
                 −6.97% 
                 −7.82% 
                 −11.25% 
               
               
                 VT07 
                 0.00% 
                 −0.52% 
                 −6.90% 
                 −9.08% 
                 9.17% 
               
               
                 VT08 
                 0.00% 
                 1.33% 
                 0.76% 
                 1.04% 
                 0.28% 
               
               
                 VT09 
                 0.00% 
                 1.17% 
                 1.75% 
                 1.56% 
                 2.34% 
               
               
                 VT10 
                 0.00% 
                 −5.56% 
                 −7.54% 
                 3.97% 
                 −2.38% 
               
               
                 VT11 
                 0.00% 
                 −7.75% 
                 −9.39% 
                 −14.55% 
                 −12.91% 
               
               
                 Average 
                 0.00% 
                 −2.23% 
                 −5.88% 
                 −2.90% 
                 −0.19% 
               
               
                 for 1.0% 
               
               
                 Average 
                 0.00% 
                 −0.92% 
                 −2.41% 
                 −3.18% 
                 −4.77% 
               
               
                 for 0.5% 
               
               
                 Average 
                 0.00% 
                 −2.69% 
                 −5.84% 
                 −7.53% 
                 −8.18% 
               
               
                 for 0.1% 
               
               
                   
               
            
           
         
       
     
     Example 14 
     Exemplary Formulation 
     A further exemplary formulation of the invention is set forth in the table below. 
     
       
         
           
               
             
               
                 TABLE 16 
               
             
            
               
                   
               
               
                 Exemplary formulation. 
               
            
           
           
               
               
               
               
               
            
               
                 INGREDIENT 
                 % (wt/wt) 
                 MW 
                 Conc (μM) 
                 Use 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Water (Aqua) 
                 77.3720%  
                   
                   
                 Solvent 
               
               
                 Caprylic/Capric 
                 4.0000% 
                   
                   
                 Solvent, Emmolient 
               
               
                 Triglyceride 
               
               
                 Glycerin 
                 2.9910% 
                   
                   
                 Humectant, solvent 
               
               
                 
                   Butyrospermum Parkii 
                 
                 2.0000% 
                   
                   
                 Emollient 
               
               
                 (Shea) Butter 
               
               
                 Heptyl Undecylenate 
                 2.0000% 
                   
                   
                 Emollient 
               
               
                 Cetearyl Olivate 
                 1.8000% 
                   
                   
                 Emulsion Stabilizer 
               
               
                 Cetyl Alcohol 
                 1.8000% 
                   
                   
                 Emulsion Stabilizer, 
               
               
                   
                   
                   
                   
                 emulsifying agents 
               
               
                 Dimethicone 
                 1.5000% 
                   
                   
                 Skin protectant, 
               
               
                   
                   
                   
                   
                 occlusive 
               
               
                 Sorbitan Olivate 
                 1.2000% 
                   
                   
                 Emulsifying agent 
               
               
                 Dimethyl Isosorbide 
                 1.0000% 
                   
                   
                 Solvent 
               
               
                 Pentylene Glycol 
                 1.0000% 
                   
                   
                 Solvent, skin 
               
               
                   
                   
                   
                   
                 penetrant 
               
               
                 Squalane 
                 1.0000% 
                   
                   
                 Occlusive 
               
               
                 Phenoxyethanol 
                 0.5000% 
                   
                   
                 Preservative 
               
               
                 Sclerotium Gum 
                 0.5000% 
                   
                   
                 Emulstion stabiliser, 
               
               
                   
                   
                   
                   
                 viscosity increasing 
               
               
                   
                   
                   
                   
                 agent 
               
               
                 Caprylyl Glycol 
                 0.2500% 
                   
                   
                 Emollient 
               
               
                 Xanthan Gum 
                 0.2000% 
                   
                   
                 Emu 
               
               
                 Trisodium 
                 0.0370% 
                   
                   
                 Chelating agent 
               
               
                 Ethylenediamine 
               
               
                 Disuccinate 
               
               
                 Ethylhexylglycerin 
                 0.1250% 
                   
                   
                 Preservative 
               
               
                 Hexylene Glycol 
                 0.1250% 
                   
                   
                 Preservative 
               
               
                 Dipotassium 
                 0.1000% 
                   
                   
                 Skin calming agent 
               
               
                 Glycyrrhizate 
               
               
                 Malassezin 
                 0.1705% 
                 273.314 
                 62.38 
                 Soup Component 
               
               
                 (AB12977) 
               
               
                 Ketomalassezin 
                 0.0360% 
                 288.305 
                 12.49 
                 Soup Component 
               
               
                 (Compound A5, CV-8819) 
               
               
                   Malassezia  Lactic 
                 0.0417% 
                 334.373 
                 12.47 
                 Soup Component 
               
               
                 Acid 
               
               
                 O52 (ABI12976) 
                 0.0360% 
                 288.348 
                 12.48 
                 Soup Component 
               
               
                 Indirubin (AB17656) 
                 0.0818% 
                 262.267 
                 31.19 
                 Soup Component 
               
               
                   Malassezia  Indole A 
                 0.0430% 
                 344.392 
                 12.49 
                 Soup Component 
               
               
                 (AB17011) 
               
               
                 Indolol(3,2-b) 
                 0.0181% 
                 254.285 
                 7.12 
                 Soup Component 
               
               
                 Carbazole 
               
               
                 dl-Indole-3-Lactic 
                 0.0256% 
                 205.212 
                 12.47 
                 Soup Component 
               
               
                 2-hydroxyl-1-(1H-indol-3-yl) 
                 0.0219% 
                 175.186 
                 12.50 
                 Soup Component 
               
               
                 ethanone 
               
               
                 Indole-3 Pyruvic Acid 
                 0.0254% 
                 203.196 
                 12.50 
                 Soup Component 
               
               
                 TOTAL: 
                   100% 
               
               
                   
               
            
           
         
       
     
     DOCUMENTS 
     
         
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     All documents cited in this application are hereby incorporated by reference as if recited in full herein. 
     Although illustrative embodiments of the present invention have been described herein, it should be understood that the invention is not limited to those described, and that various other changes or modifications may be made by one skilled in the art without departing from the scope or spirit of the invention.