Source: http://www.google.com/patents/US7863327
Timestamp: 2017-09-23 17:06:20
Document Index: 6326393

Matched Legal Cases: ['Application No. 60', 'art 1', 'Application No. 2', 'Application No. 2', 'Application No. 2', 'Application No. 99', 'Application No. 99', 'Application No. 99', 'Application No. 2', 'Application No. 2', 'Application No. 99', 'Application No. 99', 'Application No. 99', 'art 1']

Patent US7863327 - Therapeutic compounds and methods of use - Google Patents
Compounds and methods useful for chemopreventative treatment of diseases such as cancer, Alzheimer's disease, Parkinson's disease, inflammatory bowel diseases, and multiple sclerosis....http://www.google.com/patents/US7863327?utm_source=gb-gplus-sharePatent US7863327 - Therapeutic compounds and methods of use
Publication number US7863327 B2
Application number US 11/121,316
Also published as CA2335505A1, CA2335505C, EP1089724A1, EP1089724A4, EP1089724B1, EP2062577A1, US6326507, US6552075, US7288568, US8034955, US8586775, US9278913, US20020042535, US20030236303, US20050288363, US20080220057, US20080234368, US20130237721, US20140275618, WO1999065478A1
Publication number 11121316, 121316, US 7863327 B2, US 7863327B2, US-B2-7863327, US7863327 B2, US7863327B2
Inventors Gordon W. Gribble, Tadashi Honda, Michael B. Sporn, Nanjoo Suh
Patent Citations (53), Non-Patent Citations (479), Referenced by (25), Classifications (31), Legal Events (5)
US 7863327 B2
wherein R1 is a cyano group, R2 is methyl, and R3 is alkoxy.
3. The pharmaceutical composition of claim 2, wherein the composition is formulated as a hard or soft capsule, a tablet, a syrup, a suspension, a wafer, or an elixir.
4. The pharmaceutical composition of claim 3, wherein the soft capsule of the composition is a gelatin capsule.
5. The pharmaceutical composition of claim 2, wherein the composition further comprises a protective coating.
6. The pharmaceutical composition of claim 2, wherein the composition further comprises an agent that delays absorption.
7. The pharmaceutical composition of claim 2, wherein the composition further comprises an agent that enhances solubility or dispersibility.
8. A pharmaceutical composition comprising a compound of claim 1 and a liposome, wherein the compound is dispersed in the liposome.
9. A pharmaceutical composition comprising a compound of claim 1, oil and water, wherein the compound is dispersed in an oil and water emulsion or a water and oil emulsion.
11. A method of treating a disorder, wherein the disorder is breast cancer, prostate cancer, colon cancer, brain cancer, melanoma, pancreatic cancer, ovarian cancer, leukemia, or bone cancer comprising administering to said subject a therapeutically effective dosage of a compound having the formula:
wherein R1 is a cyano group, R2 is methyl, and R3 is alkoxy,
such that the disorder is treated.
12. The method of claim 11, wherein the disorder is breast cancer, prostate cancer, colon cancer, brain cancer, melanoma, pancreatic cancer, ovarian cancer, leukemia, or bone cancer.
13. The method of claim 11, wherein said subject is a mammal.
The present application is a continuation of U.S. patent application Ser. No. 10/395,372 filed Mar. 24, 2003, now U.S. Pat. No. 7,288,568 which is a continuation of U.S. patent application Ser. No. 09/927,081 filed Aug. 9, 2001, now U.S. Pat. No. 6,552,075 issued Apr. 22, 2003, which is a divisional of U.S. patent application Ser. No. 09/335,003 filed Jun. 17, 1999, now U.S. Pat. No. 6,326,507 issued Dec. 4, 2001, which claims the benefit of priority to U.S. Provisional Application No. 60/090,053 filed Jun. 19, 1998, the entire contents of which are incorporated herein by reference. Additionally, all patents, published patent applications, and other references cited throughout this specification are hereby incorporated by reference in their entireties.
This invention was made with government support under grant numbers CA-23108, RO1 CA 54494, RO1 CA 62275, KO1 CA 75154 and NS 28767, awarded by the National Institutes of Health, and DOD/AMRD Award 1796-1-6163. The government has certain rights in the invention.
Triterpenoids, biosynthesized in plants by the cyclization of squalene, are used for medicinal purposes in many Asian countries; and some, like ursolic and oleanolic acids, are known to be anti-inflammatory and anti-carcinogenic (Huang et al., 1994; Nishino et al., 1988). However, the biological activity of these naturally occurring molecules is relatively weak, and therefore the synthesis of new analogs to enhance their potency was undertaken (Honda et al., 1997; Honda et al., 1998). It was previously reported that several such synthetic analogs can suppress the de novo formation of iNOS and COX-2 in macrophages that have been stimulated by IFN-γ or LPS (Suh et al., 1998). The role of both iNOS and COX-2 as enhancers of carcinogenesis in many organs is receiving increasing attention (Ohshima et al., 1994; Tamir et al., 1996; Takahashi et al., 1997; Ambs et al., 1998; Tsujii et al., 1998; Oshima et al., 1996; Hida et al., 1998; Huang et al., 1998); suppression of either the synthesis or the activity of these enzymes is therefore a target for chemoprevention (Oshima et al., 1998; Kawamori et al., 1998). Agents which induce differentiation or suppress proliferation of premalignant or malignant cells represent yet another mechanistic approach to chemoprevention, as well as to chemotherapy, of cancer.
wherein either A or B is a double bond such that when A is a double bond, C11 has substituted thereon ═X which is an organic or inorganic moiety and when B is a double bond, C12 has substituted thereon ═X; R1 is an organic or inorganic moiety which may be substituted anywhere on the six-membered ring denoted by positions 1 through 10; R2 and R3 are hydrogen or organic or inorganic moieties, wherein an R2 group may be substituted anywhere on the structure represented in formula (I); and n is a number from 0 to 100).
In a further aspect the invention relates to triterpenoid compositions effective for modulating interferon-γ (IFN-γ)-induced NO production in macrophages, said composition having an IC50 value of at least less than 0.6 μM, preferably less than 0.001 μm.
FIG. 1 illustrates the efficacy of a composition of the invention, 2-cyano-3,12-dioxoolean-1,9-dien-28oic acid (CDDO) (denoted “TP-151”), in suppressing interleukin-1β (IL-1β)-induced COX-2 expression and prostaglandin E2 (PGE2) in human colon myofibroblast 18Co cells;
FIG. 2 is a comparison of the efficacy of various compounds on NO production induced by lipopolysaccharide (LPS) in rat microglia cells (brain macrophage cells), showing activity of TP151 favorable to that of dexamethasone, a glucocorticoid, thus indicating how a composition of the invention may be used to prevent or treat a neurodegenerative disease. “TP-82” refers to 3,11-dioxoolean-1,9-dien-28oic acid;
FIG. 3 illustrates the efficacy of TP151 in protecting in rat hippocampal neurons against toxicity induced by β-amyloid peptide, which is implicated in Alzheimer's disease;
FIG. 7 illustrates, relevant to prevention or treatment of conditions with an inflammatory component, a comparison of the efficacy of various compounds on inhibiting NO production induced by LPS and IFN-γ in primary mouse macrophages, showing activity of TP151 favorable to that of dexamethasone;
FIG. 8 is a comparison of the efficacy of various compounds on inhibiting NO production induced by IFN-γ in primary mouse macrophages;
FIG. 9 illustrates a comparison of the efficacy of various compounds on inhibiting PGE2 production induced by LPS and IFN-γ in primary mouse macrophages;
FIG. 10 illustrates a comparison of the efficacy of various compounds on suppressing IFNγ and LPS-induced iNOS and COX-2 expression in primary mouse macrophages;
FIGS. 11 (A)-(H) shows induction of differentiation by CDDO in LCDB leukemia cells (A-D), PC12 cells (E-H);
FIGS. 12 (A)-(B) shows induction of differentiation by CDDO in 3T3-L1 fibroblasts.
FIGS. 13 (A)-(B) illustrates dose-response curves for suppression of cell growth in NRP-152 and MCF-7 cells by CDDO (▪), TP-82 (◯), and oleanolic acid (●).
FIGS. 14 (A)-(E) shows inhibitory effects of triterpenoids on induction of iNOS and COX-2 in mouse macrophages and human colon fibroblasts.
As used herein, the term “electron withdrawing moiety” is known in the art, and refers to a group which has a greater electron-withdrawing than hydrogen. A variety of electron-withdrawing groups are known, and include halogens (e.g., fluoro, chloro, bromo, and iodo groups), nitro, cyano, —NR3 +, —SR2 +, —NH3 +, —SO2R, SO2Ar, —COOH, —OAr, —COOR, —OR, —COR, —SH, —SR, —OH, —Ar, and —CH═CR2, where Ar is aryl, and R represents any appropriate organic or inorganic moiety and, preferably, alkyl moiety.
As used herein, the term “amino” means —NH2; the term “nitro” means —NO2; the term “halogen” designates —F, —Cl, —Br or I; the term “thiol” means SH; and the term “hydroxyl” means —OH. Thus, the term “alkylamino” as used herein means an alkyl group, as defined above, having an amino group attached thereto. The term “alkylthio” refers to an alkyl group, as defined above, having a sulfhydryl group attached thereto. The term “alkylcarboxyl” as used herein means an alkyl group, as defined above, having a carboxyl group attached thereto.
The term “aryl” as used herein includes 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, unsubstituted or substituted benzene, pyrrole, furan, thiophene, imidazole, oxazole, triazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Aryl groups also include polycyclic fused aromatic groups such as naphthyl, quinolyl, indolyl, and the like. The aromatic ring can be substituted at one or more ring positions with such moieties, e.g., as described above for alkyl groups. Preferred aryl groups include unsubstituted and substituted phenyl groups.
As used herein, the term “subject” is intended to include living organisms in which certain conditions as described herein can occur. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. In a preferred embodiment, the subject is a primate. In an even more preferred embodiment, the primate is a human. Other examples of subjects include experimental animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows. The experimental animal can be an animal model for a disorder, e.g., a transgenic mouse with an Alzheimer's-type neuropathology. A subject can be a human suffering from a neurodegenerative disease, such as Alzheimer's disease, or Parkinson's disease.
Other abbreviations used herein are as follows: CDDO, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; DMSO, dimethyl sulfoxide; iNOS, inducible nitric oxide synthase; COX-2, cyclooxygenase-2; NGF, nerve growth factor; IBMX, isobutylmethylxanthine; FBS, fetal bovine serum; GPDH, glycerol 3-phosphate dehydrogenase; RXR, retinoid X receptor; TGF-β, transforming growth factor-β; IFN-γ, interferon-γ; LPS, bacterial endotoxic lipopolysaccharide; TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β, GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; TCA, trichloroacetic acid.
Active compounds are administered at a therapeutically effective dosage sufficient to treat a condition associated with a condition in a subject. A “therapeutically effective dosage” preferably reduces the amount of symptoms of the condition in the infected subject by at least about 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80% relative to untreated subjects. For example, the efficacy of a compound can be evaluated in an animal model system that may be predictive of efficacy in treating the disease in humans, such as the model systems shown in the Example and Figures.
R1 may be an electron-withdrawing group, e.g., cyano, aryl, and halosubstituted alkyl moieties. Preferably, R1 may include cyano, halo, or —OR′, wherein R′ is H or an organic moiety, e.g., acetyl or carboxyl group. R1 may be substituted anywhere on the six-membered ring denoted by positions 1 through 10, but in a preferred embodiment R1 is at position 2 and in a more preferred embodiment R1 is a cyano group at position 2.
In a more preferred embodiment of formula (I), B is a double bond, X is O, R3 is —OH, and R1 is a cyano group, preferably at position 2. Examples of preferred compounds include 3,11-dioxoolean-1,12-dien-28oic acid, 2-cyano-3,11-dioxoolean-1,12-dien-28oic acid and 2-cyano-3,12-dioxoolean-1,9-dien-28oic acid.
In another aspect, the invention features a triterpenoid composition effective for modulating IFN-γ-induced NO production in macrophages, said composition having an IC50 value of at least less than 0.6 μM, more preferably less than 0.001 μM.
In another aspect, the invention features a method of modulating transcription or transcription of iNOS or COX-2 genes in a subject comprises administering to a subject a pharmaceutically effective amount of a composition of formula (I), such that the transcription or translation of iNOS or COX-2 genes is modulated.
wherein Rx represents any organic or inorganic moiety, preferably methyl; and Y is preferably hydroxyl. Triterpenoids, like the steroids, are formed in nature by the cyclization of squalene, with the retention of all 30 carbon atoms in molecules such as ursolic acid (UA) and oleanoic acid (OA). Although OA and UA are known to have numerous pharmacological activities, the potency of these naturally occurring molecules is relatively weak. The derivatives of OA and UA as disclosed herein, however, are more potent than OA and UA.
In a preferred embodiment, such compounds include derivatives of ursolic acid and oleanoic acid. In a particularly preferred embodiment, derivatives of OA, e.g., 2-cyano-3,12-dioxoolean-1,9-dien-28oic acid (CDDO):
These compounds have utility for prevention and treatment of cancer, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, inflammatory bowel disease, and all other diseases whose pathogenesis is believed to involve excessive production of either nitric oxide or prostaglandins.
MS is known to be an inflammatory condition of the central nervous system (Williams, Ulvestad and Hickey, 1994; Merrill and Beneviste, 1996; Genain and Nauser, 1997). Inflammatory, oxidative, or immune mechanisms may be involved in the pathogenesis of MS, AD, PD, and ALS (Bagasra et al., 1995; Griffin et al., 1995; McGeer and McGeer, 1995; Good et al., 1996; Simonian and Coyle, 1996; Kaltschrnidt et al., 1997). Both reactive astrocytes and activated microglia have been implicated in causation of NDD/NID; there has been a particular emphasis on microglia as cells that synthesize both NO and prostaglandins as products of the respective enzymes, iNOS and COX-2. De novo formation of these enzymes may be driven by inflammatory cytokines such as interferon-gamma or interleukin-1. In turn, excessive production of NO may lead to inflammatory cascades and/or oxidative damage in cells and tissues of many organs, including neurons and oligodendrocytes of the nervous system, with consequent manifestations in AD and MS, and possible PD and ALS (Coyle and Puttfarcken, 1993; Goodwin et al., 1995; Beal, 1996; Good et al., 1996; Merrill and Benvenist, 1996; Simonian and Coyle, 1996; Vodovotz et al., 1996). Epidemiologic data indicate that chronic use of NSAID's which block synthesis of prostaglandins from arachidonate, markedly lower the risk for development of AD (McGeer et al., 1996; Stewart et al., 1997). Thus, agents that block formation of NO and prostaglandins, may be used in approaches to prevention and treatment of NDD.
The practice of the present invention will employ, unless otherwise indicated, conventional techniques of cell biology, cell culture, molecular biology, microbiology, recombinant DNA, and immunology, which are within the skill of the art. Such techniques are explained fully in the literature. See, for example, Genetics; Molecular Cloning A Laboratory Manual, 2nd Ed., ed. by Sambrook, J. et al. (Cold Spring Harbor Laboratory Press (1989)); Short Protocols in Molecular Biology, 3rd Ed., ed. by Ausubel, F. et al. (Wiley, NY (1995)); DNA Cloning, Volumes I and II (D. N. Glover ed., 1985); Oligonucleotide Synthesis (M. J. Gait ed. (1984)); Mullis et al. U.S. Pat. No: 4,683,195; Nucleic Acid Hybridization (B. D. Hames & S. J. Higgins eds. (1984)); the treatise, Methods In Enzymology (Academic Press, Inc., N.Y.); Immunochemical Methods In Cell And Molecular Biology (Mayer and Walker, eds., Academic Press, London (1987)); Handbook Of Experimental Immunology, Volumes I-IV (D. M. Weir and C. C. Blackwell, eds. (1986)); and Miller, J. Experiments in Molecular Genetics (Cold Spring Harbor Press, Cold Spring Harbor, N.Y. (1972)).
a: HCO2Et/MeONa/THF, b: PhSeCl/AcOEt; 30% H2O2/THF, c: NH2OH—HCl/EtOH/H2O, d: MeONa/MeOH/Et2O, e: KOH/MeOH, f: Jones, g: HCO2Et/MeONa/PhH, h: LiI/DMF
Compound 10 was prepared by formylation of OA (Compound 9) (Simonsen and Ross, 1957) with ethyl formate in the presence of sodium methoxide in THE (Clinton et al., 1961). Compound 7 was obtained by introduction of a double bond at C-1 of Compound 10 with phenylselenenyl chloride in ethyl acetate and sequential addition of 30% hydrogen peroxide (Sharpless et al., 1973). Compound II was synthesized from Compound 10 by addition of hydroxylamine in aqueous ethanol; cleavage of Compound II with sodium methoxide gave Compound 12 (Johnson and Shelberg, 1945). Compound 14 was prepared from Compound 13 (Picard et al., 1939) by alkali hydrolysis followed by Jones oxidation. Compound 15 was prepared by formylation of Compound 14 with ethyl formate in the presence of sodium methoxide in benzene. Compound 16 was synthesized from Compound 15 by addition of hydroxylamine. Cleavage of 16 with sodium methoxide gave Compound 17. Compound 6 (CDDO) was prepared by introduction of a double bond at C-1 of Compound 17 with phenylselenenyl chloride in ethyl acetate and sequential addition of 30% hydrogen peroxide, followed by halogenolysis with lithium iodide in DMF (Dean, P. D. G., 1965).
The inhibitory activities of these compounds and dexamethasone on IFN-γ induced NO production in mouse macrophages is shown below in Table 1. The following procedure for the assay was used. Macrophages were harvested from female mice injected intraperitoneally four days previously with 4% thioglycollate. These cells were seeded in 96-well tissue culture plates and incubated with 4 ng/mL IFN-γ in the presence or absence of inhibitory test compounds. After 48 hours NO production (measured as nitrite by the Griess reaction) was determined. Full details of the assay are given in Ding et al., 1990; Bogdan et al., 1992. Compound 6 (CDDO) showed excellent inhibitory activity (IC50, 1 nM) similar to that of dexamethasone.
2 0.9 7 <1.0b
aIC50 (μM) values of compounds 1-5, 7 and 8 were determined in the range of 0.01-40 μM (4-fold dilutions) and the ones of dexamethasone and 6 were determined in the range of 1 μM-0.1 pM (10 fold dilutions). Values are the average of two separate experiments.
bCompound 7 was very toxic above 1 μM and not active below 1 μM.
For the following examples, stock solutions of CDDO (0.01 M) were made in DMSO and aliquots frozen at −20° C. Serial dilutions were made in DMSO before addition to cell culture media. Primary rat microglia and hippocampal neurons were isolated and cultured as described by Flaris et al., 1993 and Ren and Flanders, 1996.
CDDO induces monocytic differentiation in the poorly differentiated LCDB acute myelogenous leukemia cell line, derived from a chemotherapy-resistant patient at the NCI Pediatric Oncology Branch. FIG. 11 illustrates LCDB cells seeded in RPMI 1640/2% FBS, either alone (11A), with 2.5 ng/ml TGF-β1 (11B), with 10−8M CDDO (11C), or with both TGF-β1 and CDDO (11D). After 48 h, cytospin slide preparations were made and stained for α-naphthyl acetate esterase activity (kit from Sigma). PC12 cells were cultured for 5 days in gridded dishes in DMEM/10% FBS and 5% horse serum (Smith et al., 1997), either alone (11E), with 100 ng/ml 7S NGF (11F), with 10−6 M CDDO (11G), or with both NGF and CDDO (11H). Cells were plated in triplicate, and for each treatment similar results were observed in at least two separate platings of cells. Methods for quantitative image analysis of size of cells and neurites have been described (De la Torre et al., 1997). Control cells in FIG. 11E are approximately 10 μm in diameter. 3T3-L1 cells were grown to confluency in DMEM/5% calf serum, and then treated once with CDDO in DMEM/10% FBS (FIG. 12A) or with CDDO and/or LG100268 in DMEM/10% FBS (FIG. 12B). Every two days thereafter, medium was changed to DMEM/10% FBS, without added CDDO or LG100268, Cells were harvested on day 8 (FIG. 12A) or day 6 (FIG. 12B), and GPDH was measured in lysates, using a standard assay for consumption of NADH at 340 nm (Wise and Green, 1979). These cells do not express the monocyte/macrophage marker, α-naphthyl esterase (FIG. 11A). However, within 48 h, CDDO (10−8 M) induced the activity of this enzyme, as determined histochemically (FIG. 11C). Treatment of LCDB cells with TGF-β1 (2.5 ng/ml) also induced α-naphthyl esterase activity (FIG. 11B), and there was an additive effect when both agents are used (FIG. 11D). It has been shown that CDDO has differentiative effects, either by itself or in combination with TGF-β1, on the human monocytic leukemia line, THP-1, and the human promyelocytic leukemia line, NB4 (data not shown).
The rat pheochromocytoma cell line, PC12, has been widely used to study neuronal development and differentiation. Treatment of these tumor cells with NGF is known to induce a neuronal phenotype, with extensive neurite outgrowth (Greene and Rischler, 1976; Guroff 1985). CDDO markedly potentiates these effects of NGF. FIGS. 11E and F show the induction of neurite outgrowth by NGF (100 ng/ml). Although CDDO (10−6 M) by itself does not induce neurite formation, it does cause the cells to adopt a larger, flatter morphology (FIG. 11G). When used in combination with NGF, CDDO (FIG. 11H) almost doubled the number of primary neurites/cell (from 1.2±0.2 S.E.M. to 2.1±0.1, p<0.001), and caused a greater than 3-fold increase in length of neurites (from 28±6 to 99±9 microns, p<0.001), and a 5-fold increase in neurite branching/cell (from 0.23±0.06 to 1.13±0.08, p<0.001). Thus, CDDO enhances neuronal differentiation of PC12 cells by increasing cell size, as well as the extent and complexity of neurite arborization.
A third cell type in which CDDO induces differentiation is the 3T3-L1 fibroblast. These non-neoplastic fibroblasts are classically induced to form adipocytes by the combination of insulin, dexamethasone, and IBMX (Green and Kehinde, 1974; Bernlohr et al., 1984). Treatment with CDDO (FIG. 12A) at doses as low as 10−8 M (in the absence of added insulin, dexamethasone, and IBMX) caused adipogenic differentiation, as measured by induction of the marker, GPDH (Wise and Green, 1979), known to be a key enzyme in triglyceride synthesis. The results with the enzyme assay have been confirmed by oil red O staining for fat droplets (data not shown). Furthermore, CDDO acts synergistically with the RXR-selective retinoid, LG100268 (Boehm et al., 1995) to promote adipogenic differentiation (FIG. 12B).
Inhibitors of cell proliferation are known to be useful chemopreventive and chemotherapeutic agents. CDDO was tested against a wide variety of cells derived from highly aggressive leukemias and carcinomas, as well as from non-neoplastic tissues. NRP-152 cells were grown as described in Danielpour et al., 1994. MCF-7 cells were grown in phenol red-free RPMI 1640/10% charcoal-stripped FBS with added 17-β-estradiol (10 pM). Triterpenoids were added at the time of plating, and 72 h later 3H-thymidine (1 μCi/well) was added for the final 2 h of incubation. Incorporation of thymidine was measured after cells were precipitated with TCA (10%), washed, and solubilized. The symbols used in FIGS. 13(A)-(B) are CDDO, ▪; TP-82, ◯, and oleanolic acid; ●.
Typical dose-response curves are shown in FIGS. 13(A)-(B) for two cell types, human MCF-7 breast carcinoma and rat NRP-152 non-malignant prostate epithelium (Danielpour et al., 1994). CDDO is highly active in the nanomolar range in suppressing thymidine incorporation in these cells, while TP-82 is markedly less active, and oleanolic acid, is virtually without activity at concentrations of 1 μM or less.
Results obtained with other cancer cells are shown in Table 2. Note that: (1) several lines of estrogen receptor-negative breast cancer cells are sensitive to CDDO, as well as estrogen receptor-positive MCF-7 cells; (2) even if tumor cells have a Smad-4/DPC4 mutation and are therefore insensitive to the growth-inhibitory actions of TGF-β (Schutte et al., 1996; Zhou et al., 1998; Heldin et al., 1997), they still may respond to CDDO, as can be seen in the case of SW626 ovarian carcinoma, CAPAN-1 and AsPc-1 pancreatic carcinoma, and MDA-MB-468 breast carcinoma cells; (3) many leukemia cells, especially of the myeloid lineage, are highly sensitive to CDDO.
21 -NT ER negative breast carcinoma 1 × 10−6
MDA-MB-468a ER negative breast carcinoma 2 × 10−7
SW626a Ovarian carcinoma 3 × 10−7
AsPc-1a Pancreatic carcinoma 1 × 10−7
CAPAN-1a Pacreatic carcinoma 3 × 10−7
All cells were obtained from ATCC, except as noted. They were grown under standard conditions in either DMEM, DMEM/F12, or RPMI 1640 media plus 5-10% FBS. CDDO, over the dose range 10−6 to 10−10 M, was added to cultures at the time of seeding. Three or 4 days later, cells were treated with 3H-thymidine for 2 h (12 h in the case of leukemia cells), and then incorporation was measured. “ER” means estrogen receptor.
aThese cells all have Smad4/DPC4 mutations (Schulte et al. 1996).
CDDO is highly active in blocking the ability of several inflammatory cytokines to induce de novo formation of the enzymes, iNOS and COX-2 (FIG. 14). FIG. 14(A) illustrates Western blots; primary mouse macrophages; IFN-γ, 10 ng/ml; LPS, 2 ng/ml were added to cultures together with triterpenoids or dexamethasone (concentrations shown as μM); cells were harvested at 12 h. FIG. 14(B) illustrates Northern blots, RAW 264.7 macrophage-like cell line. IFN-γ, 10 ng/ml; LPS, 1 ng/ml; TNF-α, 10 ng/ml, were added to cultures together with CDDO or dexamethasone. RNA prepared after 12 h; GAPDH used as a loading control. FIG. 14(C) illustrates suppression of production of NO and PGE2 in primary macrophages. For NO studies, cells were treated with IFN-γ, 10 ng/ml, together with CDDO (▪), dexamethasone (◯), TP-82 (□), or oleanolic acid (▴). After 48 h, supernatants were analyzed for NO by the Griess reaction. For PGE2 studies, cells were treated with IFN-γ, 5 ng/ml, and LPS, 5 ng/ml, together with the same set of inhibitors. After 48 h, PGE2 was measured in supernatants by immunoassay. Control values (no inhibition) for NO and PGE2 were 4.7 nmol/2×105 cells and 2.2 ng/ml/2×105 cells, respectively. FIGS. (14D) and (14E) illustrate (human colon myofibroblasts) 18Co cells grown in MEM/10% FBS; other methods are the same as reported above for macrophages. FIG. 14(D) illustrates Northern blots showing dose-response for suppression of COX-2 mRNA after induction with IL-1β (30 pg/ml). CDDO was added together with IL-1. In FIG. (E), Western blots show suppression of COX-2 protein; CDDO was added together with IL-1β (30 pg/ml). Also shown is suppression of cumulative production of PGE2 in cell supernatants by CDDO.
These effects of CDDO have been seen in primary mouse macrophages, a mouse macrophage-like tumor cell line (RAW 264.7), and in non-neoplastic human colon fibroblasts. FIG. 14A shows Western blots for expression of iNOS and COX-2 protein in primary macrophages. Neither iNOS nor COX-2 expression can be detected in these cells until they are stimulated by an inflammatory mediator such as IFN-γ or LPS. CDDO at concentrations of 1 μM or less blocked expression of both iNOS and COX-2 protein. The importance of the nitrile function at C-2 of CDDO, as seen above in FIG. 13, is again shown in FIG. 14A. FIG. 14B shows Northern blots indicating that CDDO (10−6 M) lowered levels of mRNA expression for both iNOS and COX-2 in RAW 264.7 cells by greater than 75%. The above effects on iNOS and COX-2 are also reflected in the cumulative production of their respective enzyme products, NO and PGE2, as measured in primary macrophages (FIG. 14C). Significant inhibition by CDDO was found at levels as low as 10−9M, and again it was markedly more active than TP-82 or oleanolic acid. However, CDDO is not a direct inhibitor of the enzymatic activity of either iNOS or COX-2, since it has no immediate effect on NO or prostaglandin production if it is added to RAW cells in which synthesis of these two enzymes has already been induced (data not shown). Likewise, the actions of CDDO are not blocked by the glucocorticoid antagonist, RU-486, which is known to bind to the glucocorticoid receptor (data not shown). In these regards, CDDO is identical to the other oleanolic acid derivatives previously studied (Suh et al., 1998).
A second type of cell in which CDDO is a highly effective inhibitor of the de novo formation of COX-2 is the colon myofibroblast. These cells were selected because of the importance of stromal cell COX-2 in colon carcinogenesis (Oshima et al., 1996). CDDO blocked induction of COX-2 mRNA and protein caused by treatment of non-neoplastic 18Co cells with IL-1 (FIGS. 14D, E); again, this action was reflected in a lowering of PGE2 levels in the culture medium. Although CDDO effectively blocks the induction of COX-2 by agents such as IFN-γ, LPS, TNF-α, and IL-1, CDDO is ineffective when TPA is used as the inducer of COX-2. This has been seen in 18Co cells, as well as in the human mammary epithelial cell line, 184B5/HER (Zhai et al., 1993).
The roles of inflammatory mediators, as well as aberrant programs for cell survival and apoptosis, in the genesis of cancer and Alzheimer's Disease are now undergoing serious investigation (McGeer and McGeer, 1995; Merrill and Benveniste, 1996; Akama et al., 1998). CDDO was tested in this example as a suppressor of de novo formation of iNOS in cultured microglia (the resident macrophages of the brain), as well as its ability to protect cultured hippocampal neurons from cell death induced by β-amyloid. It was found that CDDO acts in primary microglial cultures in a manner similar to that reported above for primary peritoneal macrophages. Thus, LPS (5 ng/ml) induced iNOS in primary microglial cultures and caused a 27-fold increase in production of NO within 18 h. Concomitant treatment of these cultures with CDDO at either 10−6 or 10−7 M inhibited this induction by 73% and 52%, respectively. We have also explored the possibility that CDDO can protect cultured hippocampal neurons from cell death induced by the peptide β-amyloid, since NO has been implicated (Akama et al., 1998) in the neurotoxic actions of this peptide which is central to the pathogenesis of Alzheimer's disease (Selkoe, 1997). Hippocampal neurons were isolated and cultured from 16 day rat embryos and then treated with CDDO for 24 h before adding the β-amyloid peptide fragment, amino acids 25-35, at a final concentration of 10 μM. This dosing with β-amyloid alone caused death of more than half of the neurons in the culture within 24 h, as measured by MTT assay. However, pretreatment of the neuronal cultures with CDDO (10−8 and 10−7 M) totally prevented this cell death, and some protective activity of CDDO was found at doses as low as 10−10 M.
As seen above, compounds of the invention such as CDDO are potent, multifunctional molecules having a wide range of actions, many of them potentially useful for prevention or treatment of diseases such as cancer. Proliferation of many human tumor cell lines, including those derived from estrogen receptor-positive and -negative breast carcinomas, myeloid leukemias, and several carcinomas that bear a Smad-4 mutation are inhibited. The ability of various inflammatory cytokines, such as interferon-γ, interleukin-1, or tumor necrosis factor-α to induce de novo formation of the enzymes, inducible nitric oxide synthase (iNOS) or inducible cyclooxygenase (COX-2) in either mouse peritoneal macrophages, rat brain microglia, or human colon fibroblasts is suppressed. Also, brain hippocampal neurons are protected from cell death induced by β-amyloid. The above indicates that the compounds of the invention, e.g., CDDO, are useful in vivo, either for chemoprevention or chemotherapy of malignancy, as well as for neuroprotection.
US4395423 Dec 6, 1979 Jul 26, 1983 Sterling Drug Inc. Polycyclic cyanoketones
US4808614 Jun 4, 1987 Feb 28, 1989 Eli Lilly And Company Difluoro antivirals and intermediate therefor
US5401838 Apr 7, 1993 Mar 28, 1995 Eli Lilly And Company Stereoselective fusion glycosylation process for preparing 2'-deoxy-2',2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides
US5426183 Apr 7, 1993 Jun 20, 1995 Eli Lilly And Company Catalytic stereoselective glycosylation process for preparing 2'-deoxy-2',2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides
US5464826 Jul 26, 1994 Nov 7, 1995 Eli Lilly And Company Method of treating tumors in mammals with 2',2'-difluoronucleosides
US5521294 Jan 18, 1995 May 28, 1996 Eli Lilly And Company 2,2-difluoro-3-carbamoyl ribose sulfonate compounds and process for the preparation of beta nucleosides
US5597124 Mar 9, 1994 Jan 28, 1997 Evt Energie- Und Verfahrenstechnik Gmbh Particle size reduction
US5603958 May 31, 1995 Feb 18, 1997 British Technology Group Limited Pharmaceutical carrier
US5606048 Nov 17, 1994 Feb 25, 1997 Eli Lilly And Company Stereoselective glycosylation process for preparing 2'-Deoxy-2', 2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides
US5972703 Aug 12, 1994 Oct 26, 1999 The Regents Of The University Of Michigan Bone precursor cells: compositions and methods
US6025395 Apr 14, 1997 Feb 15, 2000 Duke University Method of preventing or delaying the onset and progression of Alzheimer's disease and related disorders
US6326507 Jun 17, 1999 Dec 4, 2001 Trustees Of Dartmouth College Therapeutic compounds and methods of use
US6485756 Apr 6, 2000 Nov 26, 2002 Collaborative Technologies, Inc. Stable, homogeneous natural product extracts containing polar and apolar fractions
US6974801 May 12, 2003 Dec 13, 2005 The Trustees Of Dartmounth College Inhibitors and methods of use thereof
US7176237 Jan 15, 2003 Feb 13, 2007 The Trustees Of Dartmouth College Tricyclic-bis-enone derivatives and methods of use thereof
US7265096 Nov 4, 2003 Sep 4, 2007 Xenoport, Inc. Gemcitabine prodrugs, pharmaceutical compositions and uses thereof
US7288568 Mar 24, 2003 Oct 30, 2007 Trustees Of Dartmouth College Therapeutic compositions and methods of use
US7435755 Nov 28, 2001 Oct 14, 2008 The Trustees Of Dartmouth College CDDO-compounds and combination therapies thereof
US20050276836 Jul 12, 2005 Dec 15, 2005 Michelle Wilson Coated vaginal devices for vaginal delivery of therapeutically effective and/or health-promoting agents
US20050288363 May 3, 2005 Dec 29, 2005 Trustees Of Dartmouth College Therapeutic compositions and methods of use
US20070155742 Feb 7, 2007 Jul 5, 2007 Tadashi Honda Tricyclic-bis-enone derivatives and methods of use thereof
US20080220057 Oct 29, 2007 Sep 11, 2008 Trustees Of Dartmouth College Therapeutic compounds and methods of use
US20090093447 Oct 10, 2008 Apr 9, 2009 Marina Konopleva Cddo-compounds and combination therapies thereof
DE102005041613A1 Sep 1, 2005 Mar 8, 2007 Ergonex Pharma Gmbh Use of octahydro-indolo-quinoline compound in the preparation of pharmaceutical composition for the treatment and prophylaxis of gastrointestinal and endocardial disease and carcinoid syndrome
EP0272891A2 Dec 18, 1987 Jun 29, 1988 Eli Lilly And Company Immunoglobulin conjugates
EP0329348B1 Feb 10, 1989 Jul 12, 1995 Eli Lilly And Company 2',3'-Dideoxy-2',2'-difluoronucleosides
EP0376518B1 Dec 8, 1989 Nov 29, 1995 Eli Lilly And Company Phospholipid nucleosides
EP0576230B1 Jun 21, 1993 Apr 24, 1996 Eli Lilly And Company 2'-deoxy-2', 2'-difluoro(4-substituted pyrimidine) nucleosides having antiviral and anti-cancer activity and intermediates
EP0577303B1 Jun 21, 1993 Oct 1, 1997 Eli Lilly And Company Stereoselective glycosylation process
EP0712860B1 Nov 9, 1995 Dec 5, 2001 Eli Lilly And Company Process for purifying and isolating 2'-deoxy-2',2'-difluoronucleosides
WO1991015498A2 Apr 4, 1991 Oct 17, 1991 Nycomed Imaging As Nucleoside derivatives
WO1998000173A2 Jul 1, 1997 Jan 8, 1998 Pharmacia & Upjohn Company Targeted drug delivery using sulfonamide derivatives
WO1998032762A1 Jan 23, 1998 Jul 30, 1998 Norsk Hydro Asa Gemcitabine derivatives
WO1999033483A1 Dec 29, 1998 Jul 8, 1999 Enzon, Inc. Trialkyl-lock-facilitated polymeric prodrugs of amino-containing bioactive agents
WO1999065478A1 Jun 18, 1999 Dec 23, 1999 Trustees Of Dartmouth College Therapeutic compositions and methods of use
WO2000073253A1 May 12, 2000 Dec 7, 2000 Nereus Pharmaceuticals, Inc. NOVEL INTERLEUKIN-1 AND TUMOR NECROSIS FACTOR-α MODULATORS, SYNTHESES OF SAID MODULATORS AND METHODS OF USING SAID MODULATORS
WO2001001135A1 Jun 26, 2000 Jan 4, 2001 Roche Diagnostics Corporation Enzyme inhibition immunoassay
WO2002003996A1 Jul 12, 2001 Jan 17, 2002 RAJKUMAR, Sujatha Use of dammarane-type tritepenoid saporins
WO2002047611A2 Nov 28, 2001 Jun 20, 2002 Board Of Regents, The University Of Texas System Cddo-compounds and combination therapies thereof
WO2003043631A2 Nov 18, 2002 May 30, 2003 Chugai Seiyaku Kabushiki Kaisha Method for identification of tumor targeting enzymes
WO2003059339A1 Jan 15, 2003 Jul 24, 2003 Trustees Of Dartmouth College Tricyclic-bis-enone derivatives and methods of use thereof
WO2005042002A2 Nov 1, 2004 May 12, 2005 Entelos, Inc. Treatment of rhematoid arthritis with flip antagonists
WO2005046732A2 Nov 3, 2004 May 26, 2005 THE UNITED SATES OF AMERICA as represented by THE SECRETARY OF HEALTH AND HUMAN SERVICES, NIH Methods and compositions for the inhibition of hiv-1 replication
WO2006029221A2 Sep 7, 2005 Mar 16, 2006 Pacific Arrow Limited Anti-tumor compounds with angeloyl groups
WO2007005879A2 Jul 3, 2006 Jan 11, 2007 The Johns Hopkins University Compositions and methods for the treatment or prevention of disorders relating to oxidative stress
WO2007069895A1 Dec 12, 2006 Jun 21, 2007 Mosamedix B.V. Annexin derivatives suitable for pretargeting in therapy and diagnosis
WO2008111497A1 Mar 7, 2008 Sep 18, 2008 Santen Pharmaceutical Co., Ltd. Prophylactic or therapeutic agent for ophthalmic disease associated with oxidative stress, comprising triterpenoid as active ingredient
WO2008136838A1 Jun 22, 2007 Nov 13, 2008 Trustees Of Dartmouth College Novel amide derivatives of cddo and methods of use thereof
WO2009023232A1 Aug 14, 2008 Feb 19, 2009 Reata Pharmaceuticals, Inc. Novel forms of cddo methyl ester
1 "CDDO in treating patients with metastatic or unresectable solid tumors or lymphoma," http://www.clinicaltrials.gov/ct2/show/NCT00352040?term=CDDO&rank=1, Dec. 14, 2008.
2 "FDA mulls drug to slow late-stage Alzheimer's," http://www.cnn.com/2003/HEALTH/conditions/09/24/alzheimers.drug.ap/index.html, Retrieved on Sep. 23, 2003.
3 "Phase IIa trail to determine the effects of bardoxolone methyl on renal function in patients with diabetic nephropathy," http://www.clinicaltrials.gov/ct2/show/NCT00664027?term=rta&rank=10, Dec. 14, 2008.
4 "RTA 402 in advanced solid tumors or lymphoid malignancies," http://www.clinicaltrials.gov/ct2/show/NCT00508807?term =rta&rank=2&show—desc=Y, Dec. 14, 2008.
5 "Study to assess the safety, tolerability, and pharmacodynamics of RTA 402 in patients with hepatic dysfunction," http://www.clinicaltrials.gov/ct2/show/NCT00550849?term=rta&rank=4, Dec. 14, 2008.
6 Abraham and Kappas, "Heme oxygenase and the cardiovascular-renal system," Free Radic. Biol. Med., 39 (1): 1-25, 2005.
7 Agarwal and Mehta, "Possible involvement of Bcl-2 pathway in retinoid X receptor alpha-induced apoptosis of HL-60 cells," Biochem Biophys Res Commun, 230(2):251-253, 1997.
8 Ahmad et al., "Triterpenoid CDDO-Me blocks the NF-κB pathway by direct inhibition of IKKβ on Cys-179", J. Biol. Chem., 281: 35764-9, 2006.
9 Akrivakis et al., "Prolonged infusion of gemcitabine in stage IV breast cancer: a phase I study," Anti-Cancer Drugs, 10 (6): 525-531, 1999.
10 Al-alami et al., "Divergent effect of taxol on proliferation, apoptosis and nitric oxide production in MHH225 CD34 positive and U937 CD34 negative human leukemia cells," Leukemia Res., 22:939-945, 1998.
11 Alexander et al., "Synthesis and cytotoxic activity of two novel 1-dodecylthio-2-decyloxypropy1-3-phosphatidic acid conjugates with gemcitabine and cytosine arabinoside," J. Med. Chem., 46 (19): 4205-4208, 2003.
12 Alexander et al., "Synthesis and cytotoxic activity of two novel 1-dodecylthio-2-decyloxypropyl-3-phosphatidic acid conjugates with gemcitabine and cytosine arabinoside," J. Med. Chem., 46 (19): 4205-4208, 2003.
13 Ambs et al., "p53 and vascular endothelial growth factor regulate tumor growth of NOS2-expressing human carcinoma cells," Nat. Med., 4(12):1371-1376, 1998.
14 Amstutz et al., "Die position 5 im oxotremorin-gerust: eine zentrale stelle fur die steuerung der aktivitat am muscarinischen rezeptor," Helv. Chim. Acta., 70:2232-2244, 1987.
15 Andreeff et al., "Expression of bcl-2-related genes in normal and AML progenitors: Changes induced by chemotherapy and cationic acid," Leukemia, 13:1881-1892, 1999.
16 Andreeff et al., "PPARgamma nuclear receptor as a novel molecular target in leukemias," 2002 Keystone Symposia , Abstract No. 501, 2002.
17 Andreeff, "Acute myeloid leukemia," In: Cancer Treatment, Haskell (Ed.), W. B. Saunders, 911-922, 1995.
18 Araujo et al., "Systemic rather than local heme oxygenase-1 overexpression improves cardiac allograft outcomes in a new transgenic mouse," J. Immunol., 171 (3): 1572-1580, 2003.
19 Ardestani et al., "Effects of dexamethasone and betamethasone as COX-2 gene expression inhibitors on rigidity in a rat model of Parkinson's disease," Indian J. Pharmacol., 39:235-9, 2007.
20 Ariga et al., "Role of sphingolipid-mediated cell death in neurodegenerative diseases," Journal of Lipid Research, 39:1-16, 1998.
21 Bach, "Heme oxygenase-1 and transplantation tolerance," Hum. Immunol., 67 (6): 430-432, 2006.
22 Baeuerle, "NF-κB: ten years after," Cell, 87:13-20, 1996.
23 Bagasra et al., "Activation of the inducible form of nitric oxide synthase in the brains of patients with multiple sclerosis," Proc. Natl. Acad. Sci. USA, 92:12041-12045, 1995.
24 Baker et al., "2′-Deoxy-2′-methylenecytidine and 2′-deoxy-2′,2′-difluorocytidine 5′-diphosphates: potent mechanism-based inhibitors of ribonucleotide reductase," J. Med. Chem., 34 (6): 1884, 1991.
25 Baldwin, Jr., "The Nf-κB and IκB proteins: new discoveries and insights," Annu. Rev. Immunol., 14:649-681, 1996.
26 Balkwill et al., "Smoldering and polarized inflammation in the initiation and promotion of malignant disease," Cancer Cell, 7 (3): 211-217, 2005.
27 Bargou et al., "Constitutive nuclear factor κB-RelA activation is required for proliferation and survival of Hodgkin's disease tumor cells," J. Clin. Invest., 100:2961-2969, 1997.
28 Barkett and Gilmore, "Control of apoptosis by Rel/NF-κB transcription factors," Oncogene, 18:6910-6924, 1999.
29 Barnes and Karin, "Nuclear factor-κB—a pivotal transcription factor in chronic inflammation diseases," N. Engl. J. Med., 336:1066-1071, 1997.
30 Beal, "Mitochondria, free radicals, and neurodegeneration," Curr. Opin. Neurobiol., 6:661-666, 1996.
31 Begum et al., "Synthesis of 2β-hydroxyursolic acid and other ursane analogs from ursonic acid," Australian Journal of Chemistry, 46 (7): 1067-1071, 1993.
32 Beran et al., "Topotecan and cytarabine is an active combination regimen in myelodysplastic syndromes and chronic myelomonocytic leukemia," J. Clinical Oncology, 17(9):2819-2830, 1999.
33 Bliard et al., "Glycosylation of acids under phase transfer conditions. Partial synthesis of saponins," Tetrahedron Lett., 35:6107-6108, 1994.
34 Bogdan et al., "Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10," J. Biol. Chem., 267:23301-23308, 1992.
35 Bogdon and Ding, "Taxol, a microtubule-stabilizing antineoplastic agent, induces expression of tumor necrosis factor alpha and interleukin-1 in macrophages," J. Leukoc. Biol., 52(1):119-121, 1992.
36 Bogdon and Ding, "Taxol, a microtubule-stabilizing antineoplastic agent, induces expression of tumor necrosis factor α and interleukin-1 in macrophages," J. Leukoc. Biol., 52(1):119-121, 1992.
37 Bollag and Holdener, "Retinoids in cancer prevention and therapy," Annals of Oncology, 3:513-526, 1992.
38 Boolbol et al., "Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis," Cancer Res., 56(I1):2556-2560, 1996.
39 Bore et al., "The anti-inflammatory triterpenoid methyl 2-cyano-3, 12-dioxoolean 1,9(11)-dien-28-oate methanol solvate hydrate," Acta Crystallorg C., 58(Pt 3):o199-o200, 2002.
40 Bowden et al., "Constituents of the fruit of Pseudopanax arboreum (Araliaceae)," Australian J. of Chemistry, 28 (1): 91-107, 1975.
41 Brookes et al., "The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid and its derivatives elicit human lymphoid cell apoptosis through a novel pathway involving the unregulated mitochondrial permeability transition pore," Cancer Res., 67:1793-1802, 2007.
42 Bruder and Caplan, "First Bone Formation and the Dissection of an Osteogenic Lineage in the Embryonic Chick Tibia is Revealed by Monoclonal Antibodies Against Osteoblasts," Bone, 10:359-375, 1989.
43 Bruder and Caplan, "Terminal Differentiation of Osteogenic Cells in the Embryonic Chick Tibia is Revealed by a Monoclonal Antibody Against Osteocytes," Bone, 11:189-198, 1990.
44 Bruder et al., "Terminal Osteogenic Cell Differentiation in Culture Requires Beta-Glycerol Phosphate," Trans. Ortho. Res. Soc., 16:58, 1991.
45 Bruland et al., "Expression and characteristics of a novel human osteosarcoma-associated cell surface antigen," Cancer Res., 48:5302-5308, 1988.
46 Buzoni-Gatel et al., "Intraepithelial lymphocytes traffic to the intestine and enhance resistance to Toxoplasma gondii oral infection," J. Immunol., 162:5846-5852, 1999.
47 Buzoni-Gatel et al., "Murine ileitis after intracellular parasite infection is controlled by TGF-beta-producing intraepithelial lymphocytes," Gastroenterolog, 120:914-924, 2001.
48 Cai and Vasella, "A new protecting group for alkynes: orthogonally protected dialkynes," Helv. Chim. Acta., 78:732-757, 1995.
49 Campbell et al., "Endocyclic α,β-unsaturated ketones. VI. Ultraviolet and infrared absorption spectra and resonance stabalization," Bioorganic and Medicinal Chemistry Letters, 7(13): 1623-1628, 1997.
50 Carter et al., "Expression of survivin, a member of the inhibitor of apoptosis (IAP) family of caspase inhibitors is expressed in AML and regulated by cytokines and ATRA," Blood, 94(Suppl 1):479a, Abstract # 2142, 1999.
51 Cassady and Suffness, In Anticancer Agents Based on Natural Product Models; Academic Press, NY, 254-269, 1980.
52 Castaigne et al., "All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia," Blood, 76(9):1704-1709, 1990.
53 Cerwenka and Swain, "TGF-β1: immunosuppressant and viability factor for T lymphocytes," Microbes and Infection, 1: 1291-1296, 1999.
54 Chattopadhyay et al., "Studies on autoxidation: Part IV. Synthesis of isomeric 2,3-diols of olean-12-en-28-oate and isohopane (moretane)," Indian J. of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 15 (1): 21-24, 1977.
55 Chauhan et al., "The bortezomib/proteasome inhibitor PS-341 and triterpenoid CDDO-Im induce synergistic anti-multiple myeloma (MM) activity and overcome bortezomib resistance," Blood, 103:3158-3166, 2004.
56 Chen et al., "Chondrogenesis in Chick Limb Bud Mesodermal Cells: Reciprocal Modulation by Activin and Inhibin," Exp. Cell. Res., 206:119-27, 1993.
57 Chen et al., "Stimulation of chondrogenesis in limb bud mesoderm cells by recombinant human bone morphogenetic protein 2B (BMP-2B) and modulation by transforming growth factor beta 1 and beta 2," Exp. Cell. Res., 195:509-15, 1991.
58 Cheng et al., "Differentiation of Human Bone Marrow Osteogenic Stromal Cells in Vitro: Induction of the Osteoblast Phenotype by Dexamethasone," Endocrinology, 134:277-86, 1994.
59 Chintharlapalli et al., "2-Cyano-3,12-dioxoolean-1,9-dien-28-oic acid and related compounds inhibit growth of colon cancer cells through peroxisome proliferator-activated receptor gamma-dependent and -independent pathways," Mol. Pharmacol., 68:119-128, 2005.
60 Cho et al., "The transcription factor NRF2 protects against pulmonary fibrosis," FASEB Journal, 18:1-29, 2004.
61 Chou et al., "Sterospecific Synthesis of 2-Deoxy-2, 2-difluororibonolactone and its Use in the Preparation of 2′-Deoxy-2′, 2′-difluoro-B—D-ribofuranosyl Pyrimidine Nucleosides: The Key Role of Selective Crystallization," Synthesis, 565-570, 1992.
62 Chung and Wasicak, "Synthesis of chiral ∀-acetylenic cyclic amines from ∀-amino acids: App.s to differentially constrained oxotremorine analogues as muscarinic agents," Tetrahedron Lett., 31:3957-3960, 1990.
63 Cianchi et al., "Cyclooxygenase-2 activation mediates theproangiogenic effect of nitric oxide in colorectal cancer," Clinical Cancer Research, 10:2694-2704, 2004.
64 Clinton et al., "Steroidal[3,2-c]pyrazoles. II. Androstanes, 19-norandrostanes and their unsaturated analogs," J. Am Chem Soc., 83:1478-1491, 1961.
65 Corey and Ruden, "Stereoselective methods for the synthesis of terminal cis and trans enyne units," Tetrahedron Lett., 1495-1499, 1973.
66 Coyle and Puttfarcken, "Oxidative stress, glutamate, and neurodegenerative disorders," Science, 262:689-695, 1993.
67 Cripe, "Adult Acute Leukemia," Current Problems in Cancer, 21 (1): 4-64, 1997.
68 Cui, "A material science perspective of pharmaceutical solids," Int. J. Pharmceutics, 339 (1-2): 3-18, 2007.
69 Dean et al., "Halogenolysis of methyl glycyrrhetate with lithium iodidedimethylformamide," J. Chem. Soc., 6655-6659, 1965.
70 Devi et al., "Constituents of black dammar resin and some transformation products of aα- and and β-amyrins," Indian J. of Chemistry, 7 (12): 1279-1280, 1969.
71 Dezulbe et al., "Interim results of a phase I trial with a novel orally administered synthetic triterpenoid RTA 402 (CDDO-Me) in patients with solid tumors and lymphoid malignancies," J. Clin. Oncol., 2007 ASCO Annual Meeting Proceedings, 25(18S):14101, 2007.
72 Di Stefano et al., "Inhibition of [3H]thymidine incorporation into DNA of rat regenerating liver by 2′,2′-difluorodeoxycytidine coupled to lactosaminated poly-L-lysine," Biochem. Pharmacol., 57 (7): 793-799, 1999.
73 Ding et al., "Macrophage deactivating factor and transforming growth factors-beta1, beta2, and beta3 inhibit induction of macrophage nitrogen oxide synthesis by IFN-gamma," J. Immunol., 940-944, 1990.
74 Dinkova-Kostova et al., "Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress," PNAS, 102:4584-4589, 2005.
75 Drach et al., "Induction of differentiation in myeloid leukemia cell lines and acute promyelocytic leukemia cells by liposomal all-trans-retinoic acid," Cancer Research, 53:2100-2104, 1993.
76 Dragnev et al., "The retinoids and cancer prevention mechanisms," The Oncologist, 5:361-368, 2000.
77 Drefahl and Huneck, "Nor-olea-12-enol-17-amin und Olea-12-enol-28-amin," Chem. Ber., 91:278-281, 1958.
78 DuBois et al., "G1 delay in cells overexpressing prostaglandin endoperoxide synthase-21," Cancer Res., 56(4):733-737, 1996.
79 DuBois et al., "Increased cyclooxygenase-2 levels in carcinogen-induced rat colonic tumors," Gastroenterology, 110:1259-1262, 1996.
80 Dutcher et al., "Pentacyclic triterpene synthesis. 5. Synthesis of optically pure ring AB precursors," J. Org. Chem., 41:2663-2669, 1976.
81 Ekmekcioglu et al., "Tumor iNOS predicts poor survival for stage III melanoma patients," Int. J. Cancer, 119:861-866, 2006.
82 Elgamal et al., "Glycyrrhetic acid derivatives with modified ring A," J. of Pharmaceutical Sciences, 62 (9): 1557-1558, 1973.
83 Elgamal et al., "The C-2,C-3-glycol derivatives of glycyrrhetic acid," Tetrahedron, 30 (23/24): 4083-4087, 1974.
84 Ellies et al., "Mammary tumor latency is increased in mice lacking the inducible nitric oxide synthase," Int. J. Cancer, 106:1-7, 2003.
85 Elliot et al., "The triterpenoid CDDO inhibits expression of matrix metalloproteinase-1, matrix metalloproteinase-13 and Bcl-3 in primary human chondrocytes," Arthritis Res. Ther., 5:R285-R291, 2003.
86 Elsawa et al., "Preferential Inhibition of Malignant Cell Growth by CDDO in Waldenstrom Macroglobulinemia," Blood, 108(11):2528, 2006.
87 Elstner et al., "Ligands for peroxisome proliferator-activated receptorgamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice," Proc. Natl. Acad. Sci. USA, 95:8806-8811, 1998.
88 Embleton et al., "Antitumour reactions of monoclonal antibody against a human osteogenic-sarcoma cell line," Br. J. Cancer, 43:4801-4805, 1981.
89 Endová et al., "Preparation of 2,3-secodiacids of the lupane series," Collection of Czechoslovak Chemical Communications, 59 (6): 1420-1429, 1994.
90 Engel et al., "Quantitation of minimal residual disease in acute myelogenous leukemia and myelodysplastic syndromes in complete remission by molecular cytogenetics of progenitor cells," Leukemia, 13:568-577, 1999.
91 Estey et al., "Molecular remissions induced by liposomal-encapsulated all-trans retinoic acid in newly diagnosed acute promyelocytic leukemia," Blood, 94:2230-2235, 1999.
92 Estey et al., "Randomized phase II study of fludarabine + cytosine arabinoside + idarubicin + all-trans retinoic acid + granulocyte-colony stimulating factor in poor prognosis newly diagnosed acute myeloid leukemia and myelodysplastic syndrom," Blood, 93(8):2478-2484, 1999.
93 Evers et al., "Betulinic acid derivatives: a new class of human immunodeficiency virus type 1 specific inhibitors with a new mode of action," J. of Medicinal Chemistry, 39 (5): 1056-1068, 1996.
94 Favaloro, Jr. et al., "Design and synthesis of tricyclic compounds with enone functionalities in rings A and C: a novel class of highly active inhibitors of nitric oxide production in mouse macrophages," J Med Chem, 45(22):4801-4805, 2002.
95 Finkbeiner and Stiles, "Chelation as a driving force in organic reactions. IV. Synthesis of a ∀-nitro acids by control of the carboxylastion-decarboxylation equilibrum," J. Am. Chem. Soc., 85:616-622, 1963.
96 Finlay et al., "The effects of A and C ring modification of oleanolic and ursolic acid on the inhibition of nitric oxide formation in mouse macrophages," 213th ACS National Meeting, San Francisco, California, abstract, Apr. 13-17, 1997.
97 Finlay et al., "The effects of A and C ring modification of oleanolic and ursolic acid on the inhibition of nitric oxide formation in mouse macrophages," 213th ACS National Meeting, San Francisco, California, poster, Apr. 13-17, 1997.
98 Gandhi et al., "Prolonged infusion of gemcitabine: clinical and pharmacodynamic studies during a phase I trial in relapsed acute myelogenous leukemia," J. Clin. Oncol., 20 (3): 665-673, 2002.
99 Ganguly et al., "Oxidation of ring in a lupeol," Tetrahedron, 22 (10): 3597-3599, 1966.
100 García-Granados et al., "Semi-synthesis of triterpene A-ring derivatives from oleanolic and maslinic acids. Part II. Theoretical and experimental 13C chemical shifts," J. of Chemical Research, Synopses, 5: 211-212, 2000.
101 Garcia-Granados et al., "Semi-synthesis of triterpene A-ring derivatives from oleanolic and maslinic acids. Theoretical and experimental 13C chemical shifts," J. of Chemical Research, Synopses, 2: 56-57, 2000.
102 Genain and Hauser, "Creation of a model for multiple sclerosis in Callithrix jacchus marmosets," J. Mol. Med., 75:187-197, 1997.
103 Ghosh et al., "NF-κB and Rel proteins: evolutionarily conserved mediators of immune response," Annu Rev Immunol., 16:225-260, 1998.
104 Glen et al., "Isolation of a new triterpenoid from rose-bay willow-herb," Chemistry and Industry, London, United Kingdom), 46: 1908, 1965.
105 Godoy et al., "Central and systemic IL-I exacerbates neurodegeneration and motor symptoms in a model of Parkinson's disease," Brain, 131:1880-1894, 2008.
106 Govindachari et al., "Gymnosporol, a new pentacyclic triterpene from Gymnosporia rothiana," Indian Journal of Chemistry, 8 (5): 395-397, 1970.
107 Green and Long, "Compounds related to the steroid hormones. Part II. The action of hydrogen bromide on 2-bromo-3-oxo-Δ1-5α-steroids," J. of the Chemical Society, 2532-2543, 1961.
108 Grieco and Speake, "Synthetic Studies on Quassinoids: Total Synthesis and Biological Evaluation of (+)-Des-D-chaparrinone," J Org. Chem., 63:5929-5936, 1998.
109 Grieco and Speake, "Synthetic Studies on Quassinoids: Total Synthesis and Biological Evaluation of (+)-Des-D-chaparrinone,"J. Org. Chem., 63:5929-5936, 1998.
110 Guo et al., "Selective Protection of 2′,2′-Diflurodeoxycytidine (Gemcitabine),"J. Org. Chem., 64: 8319-8322, 1999.
111 Guo et al., "Targeted delivery of a peripheral benzodiazepine receptor ligand-gemcitabine conjugate to brain tumors in a xenograft model," Cancer Chemother. Pharmacol., 48 (2): 169-176, 2001.
112 Gura et al., "Systems for identifying new drugs are often faulty," Science, 278:1041-1042, 1997.
113 Guttridge et al., "NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1," Mol. Cell. Biol., 19 (8): 5785-5799, 1999.
114 Hail et al., "Evidence supporting a role for calcium in apoptosis induction by the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO)," J. Biol. Chem., 279:11179-11187, 2004.
115 Hanna and Ourisson, "Studies of cyclic ketones. VIII. Preparation and properties of polycyclic α-diketones," Bulletin de la Societe Chimique de France, 1945-1951, 1961. (French only, but see attached English CAPLUS database summary.).
116 Hattori et al., "A triterpene from the fruits of Rubus chingii," Phytochemistry, 27 (12): 3975-3976, 1988.
117 Heiner et al., "Localization of GD2-specific monoclonal antibody 3F8 in human osteosarcoma," Cancer Res., 47:5377-5384, 1987.
118 Hidvegi et al., "A low temperature method of isolating normal human articular chondrocytes," Osteoarthr. Cartil., 14:89-93, 2006.
119 Hinz et al., "NF-kappaB function in growth control: regulation of cyclin D1 expression and G0/G1-to-S-phase transition," Mol. Cell. Biol., 19 (4): 2690-2698, 1999.
120 Hirota et al., "Stereoselective total synthesis of (±)-eperuane-8β,15-diol1," Bull. Chem. Soc. Jpn., 61:4023-4028, 1988.
121 Hirota et al., "Suppression of tumor promoter-induced inflammation of mouse ear by ursolic acid and 4,4-dimethycholestane derivatives " Agric. Biol. Chem., 54:1073-1075, 1990.
122 Hirota et al., "Total synthesis of (±)-amarolide, a quassinoid bitter principle," J. Org. Chem., 56:1119-1127, 1991.
123 Hirota et al.,"Suppression of tumor promoter-induced inflammation of mouse ear by ursolic acid and 4,4-dimethycholestane derivatives" Agric. Biol. Chem., 54:1073-1075, 1990.
124 Honda et al., "A novel dicyanotriterpenoid, 2-cyano-3, 12-dioxooleana-1,9(11)-dien-28-onitrile, active at picomolar concentrations for inhibition of nitric oxide production," Bioorgainc & Medicinal Chemistry Letters, 12:1027-1030, 2002.
125 Honda et al., "An Efficient Synthesis of Tricyclic Compounds, (±)-(4aβ,8aβ,10aα)-1,2,3,4,4a,6,7,8,8a,9,10,10a,- Dodecahydro-1,1,4a-Trimethyl-2-Oxophenanthrene-8a-Carboxylic Acid, its Methyl Ester, and (±)-(4aβ,8aβ,10aα)-3,4,4a,6,7,8,8a,9,10,10a-Decahydro-8a-Hydroxymethyl-1,1,4a-Trimethylphenanthren-2(1H)-One," Org. Prep. Proced. Int., 37:546-550, 2005.
126 Honda et al., "Design and synthesis of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, a novel and highly active inhibitor of nitric oxide production in mouse macrophages," Bioorg Med Chem Lett., 8(19):2711-2714, 1998.
127 Honda et al., "Design, synthesis, and biological evaluation of biotin conjugates of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid for the isolation of the protein targets," J. Med. Chem., 47 (20): 4923-4932, 2004.
128 Honda et al., "Efficient synthesis of (−)- and (+)-tricyclic compounds with enome functionalities in rings A and C. A novel class of orally active anti-inflammatory and cancer chemopreventive agents," Org Biomol Chem, 1:4384-4391, 2003.
129 Honda et al., "New enone derivatives of oleanolic acid and ursolic acid as inhibitors of nitric oxide production in mouse macrophages," Bioorg. Med. Chem. Lett., 7:1623-1628, 1997.
130 Honda et al., "New synthetic oleanane and ursane triterpenoids as inhibitors of nitric oxide production in mouse macrophages," 5th Chemical Congress of North America Meeting, Cancun, Mexico, abstract, Nov. 11-15, 1997.
131 Honda et al., "New synthetic oleanane and ursane triterpenoids as inhibitors of nitric oxide production in mouse macrophages," 5th Chemical Congress of North America Meeting, Cancun, Mexico, slides from oral presentation and poster, Nov. 11-15, 1997.
132 Honda et al., "Novel synthetic oleanane and ursane triterpenoids with various enone functionalities in ring a as inhibitors of nitric oxide production in mouse macrophages," J. Med. Chem., 43:1866-1877, 2000.
133 Honda et al., "Novel synthetic oleanane triterpenoids: a series of highly active inhibitors of nitric oxide production in mouse macrophages," Bioorg Med Chem Lett, 9(24):3429-3434, 1999.
134 Honda et al., "Novel tricyclic compounds having acetylene groups at C-8a and cyano enones in rings A and C: highly potent anti-inflammatory and cytoprotective agents," J. Med. Chem., 50:1731-1734, 2007.
135 Honda et al., "Synthesis of (±)-3,3-ethylenedioxy-14α-hydroxy-5-picrasene-11,16-dione, a 14αH-picrasane derivative," Chem. Lett., 299-302, 1981.
136 Honda et al., "Synthesis of a novel dicyano abietane analogue: a potential antiinflammatory agent," J. Org. Chem., 71:3314-3316, 2006.
137 Honda et al., "Synthetic oleanane and ursane triterpenoids with modified rings A and C: a series of highly active inhibitors of nitric oxide production in mouse macrophages," J. Med. Chem., 43:4233-4246, 2000.
138 Hong et al., "Phase I trial of a novel oral Nf-κB/pSTAT3 inhibitor RTA-402 in patients with solid tumors and lymphoid malignancies," 44th Annual Meeting of the American Society of Clinical Oncology, 2008.
139 Hosoi et al., "Detection of human osteosarcoma-associated antigen(s) by monoclonal antibodies," Cancer Res., 42:654-661, 1982.
140 Huang et al., "Inhibition of skin tumorigenesis by Rosemary and its constituents carnosol and ursolic acid," Cancer Res., 54:701-708, 1994.
141 Huang et al., "Inhibitory effects of dietary curcumin on forestomach, duodenal, and colon carcinogenesis in mice," Cancer. Res., 54:5841-5847, 1994.
142 Huang et al., "Structure of a WW domain containing fragment of dystrophin in complex with β-dystroglycan," Nat. Struct. Biol., 7:634-638, 2000.
143 Huneck, "Triterpene, XIV: die bromierung von 19β328-epoxy-3-oxo-2-diazo- and -1-oxo-2-diazo- sowie von 19β328-epoxy-IU-oxo-18βH-oleanan," Chemische Berichte, 98 (9): 2837-2843, 1965. (German only, but see attached English CAPLUS database summary.).
144 Hyer et al., "Synthetic triterpenoids cooperate with tumor necrosis factor-related apoptosis-inducing ligand to induce apoptosis of breast cancer cells," Cancer Res., 65:4799-4808, 2005.
145 Iguchi et al., "Lipid peroxidation and disintegration of the cell membrane structure in cultures of rat lung fibroblasts treated with asbestos," J. Appl. Toxicol., 13:269-275, 1993.
146 Ikeda et al., "Induction of redox imbalance and apoptosis in multiple myeloma cells by the novel triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid," Mol. Cancer Ther., 3:39-45, 2004.
147 Ikeda et al., "The novel triterpenoid CDDO and its derivatives induce apoptosis by disruption of intracellular redox balance," Cancer Res., 63:5551-5558, 2003.
148 Ishikawa et al., "Heme oxygenase-1 inhibits atherogenesis in Watanabe heritable hyperlipidemic rabbits," Circulation, 104 (15): 1831-1836, 2001.
149 Ito et al., "Involvement of caspase-8 in the induction of osteosarcoma cell apoptosis by the novel triterpenoid CDDO," 47th Annual Meeting, Orthopaedic Research Society, Feb. 25-28, 2001, San Francisco, California, p. 0863, Poster Session, 2001.
150 Ito et al., "The novel triterpenoid 2-cyano-3, 12-dioxoolean-1,9-dien-28-oic acid induces apoptosis of human myeloid leukemia cells by a caspase-8-dependent mechanism," Cell Growth & Differentiation, 11(5):261-267, 2000.
151 Ito et al., "The novel triterpenoid CDDO induces apoptosis and differentiation of human osteosarcoma cells by a caspase-8 dependent mechanism," Mol. Pharmacol., 59:1094-1099, 2001.
152 Johansen et al., "Pharmacology and preclinical pharmacokinetics of the triterpenoid CDDO methyl ester," Proc. Amer. Assoc. Cancer Res., 44:1728, 2003.
153 Johnson et al., "A plan for distinguishing between some five- and six-membered ring ketones," J. Am Chem. Soc., 67:1745-1754, 1945.
154 Johnson et al., "Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials," Br. J. Cancer, 84:1424-1431, 2001.
155 Joyce et al., "Integration of Rac-dependent regulation of cyclin D1 transcription through a nuclear factor-kappaB-dependent pathway," J. Biol. Chem., 274 (236): 25245-25249, 1999.
156 Kahne and Collum, "Kinetic cyanations of ketone enolates," Tetrahedron Lett., 22:5011-5014, 1981.
157 Kaltschmidt et al ,"Transcription factor NF-kappaB is activated in primary neurons by amyloid beta peptides and in neurons surrounding early plaques from patients with Alzheimer disease," Proc. Natl. Acad. Sci. USA, 94:2642-2647, 1997.
158 Kaltschmidt et al.,"Transcription factor NF-kappaB is activated in primary neurons by amyloid beta peptides and in neurons surrounding early plaques from patients with Alzheimer disease," Proc. Natl. Acad. Sci. USA, 94:2642-2647, 1997.
159 Karin, "Nuclear Factor-iappaB in cancer development and progression," Nature, 441:431-436.
160 Karin, "Nuclear factor-kappaB in cancer development and progression," Nature, 441:431-436.
161 Kasinski et al., "Inhibition of IkappaB kinase-nuclear factor-kappaB signaling pathway by 3,5-bis(2-flurobenzylidene)piperidin-4-one (EF24), a novel monoketone analog of curcumin," Mol. Pharmacology, 74 (3): 654-661, 2008.
162 Kawamori et al., "Chemopreventive activity of celecoxib, as specific cyclooxygenase-2 inhibitor, against colon carcinogenesis," Cancer Res., 58(3):409-412, 1998.
163 Kerwin et al., "Quassinoid synthesis. 2. Preparation of a tetracyclic intermediate having the Bruceantin tetrahydrofuran ring," J. Org. Chem., 52:1686-1695, 1987.
164 Khan et al., "A dichotomous role for nitric oxide during acute Toxoplasma gondii infection in mice," Proc. Natl. Acad. Sci. USA, 94:13955-13960, 1997.
165 Khan et al., "β-amyrin derivatives from Corchorus depressus," Phytochemistry, 30 (6): 1989-1992, 1991.
166 Kim et al., "Capasase-3 activation is involved in apoptosis induced by a synthetic triterpenoid in Non-small cell lung cancer (NSCLC) cells," Proc. Amer. Assoc. Cancer Res., 41:770, Abstract #4894, 2000.
167 Kim et al., "Identification of a novel synthetic triterpenoid, methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate, that potently induces caspace-mediated apoptosis in human lung cancer cells," Molecular Cancer Therapeutics, 1:177-184, 2002.
168 Kircher, "Triterpenes, in organ pipe cactus," Phytochemistry, 19:2707-2712, 1980; Database CAPLUS on STN AN:1981:550946.
169 Klinot and Vystrcil, "Triterpenes. VII. Stereochemistry of 2-bromo derivatives of allobetuline and alloheterobetaline," Collection of Czechoslovak Chemical Communications, 31 (3): 1079-1092, 1966.
170 Klinot et al., "Triterpenes. Part LXXXVI. Triterpenoid 2,3-ketolis, diols and their acetates: preparation and conformation of the ring A," Collection of Czechoslovak Chemical Communications, 54 (2): 400-412, 1989.
171 Klotz et al., "Selective expression of inducible nitric oxide synthase in human prostate carcinoma," Cancer, 82:1897-1903, 1998.
172 Konopleva and Andreeff, "Regulatory pathways in programmed cell death," Cancer Mol Biol., 6:1229-1260, 1999.
173 Konopleva et al., "Activation of nuclear transcription factor PPARgamma by the novel triterpenoid CDDO as targeted therapy in breast cancer," 2002 Keystone Symposium, Abstract No. 539, 2002.
174 Konopleva et al., "Apoptosis: molecules and mechanisms," Adv Exp Med Biol, 457:217-236, 1998.
175 Konopleva et al., "Engraftment potential of AML progenitors into NOD/scid mice is dependent on baseline CXCR4 expression," Blood, 94(Suppl 1):166b, Abstract #3916, 1999.
176 Konopleva et al., "Mechanisms and Activity of PPARgamma-Active Triterpenoids CDDO and CDDO-Me in Leukemias," Blood, 106:2460, 2005.
177 Konopleva et al., "Novel synthetic triterpenoid CDDO-Me: potent antiproliferative, proapoptotic and differentiating agent in AML," Blood, 96(11), Part 1: 121A, abstract # 522, 2000.
178 Konopleva et al., "Novel synthetic triterpenoid, CDDO, and its methyl ester: Potent antiproliferative, proapoptotic and differentiating agents in AML," Blood, 94(Suppl 1):479a, Abstract #2140, 1999.
179 Konopleva et al., "Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia," Blood, 99(1):326-335, 2002.
180 Konopleva et al., "Peroxisome proliferator-activated receptor gamma and retinoid X receptor ligands are potent inducers of differentiation and apoptosis in leukemias," Mol. Cancer Ther., 3:1249-1262, 2004.
181 Konopleva et al., "PPARgamma Ligand CDDO Induces Apoptosis in Leukemias Via Multiple Apoptosis Pathways," Abstracts of the 44th Annual Meeting of the American Society of Hematology, Abstract No. 2209, 2002.
182 Konopleva et al., "PPARgamma Ligands Are Potent Inducers of Apoptosis in Leukemias and Lymphomas," American Society of Hematology 43rd Annual Meeting and Exposition, Abstract No. 501, 2001.
183 Konopleva et al., "PPARgamma Nuclear Receptor as a Novel Molecular Target in Leukemia Therapy," Proc. Amer. Assoc. Cancer Res., 43:4730, 2002.
184 Konopleva et al., "PPARgamma nuclear receptor as a novel therapeutic target in AML," Blood, 96(11):460a, Abstract #1982, 2000.
185 Konopleva et al., "PPARgamma Nuclear Receptor as a Novel Therapeutic Target in AML," Proc. Amer. Assoc. Cancer Res., 42:4458, 2001.
186 Konopleva et al., "PPARγ nuclear receptor as a novel therapeutic target in AML," Blood, 96(11):460a, Abstract #1982, 2000.
187 Konopleva et al., "Suppression of ERK Activation is Required for Triterpenoid Methyl-CDDO-Induced Apoptosis in AML," Blood, 102(11):1404, 2003.
188 Konopleva et al., "Synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces growth arrest in HER2-overexpressing breast cancer cells," Mol. Cancer Ther., 5:317-328, 2006.
189 Konopleva et al., "Synthetic triterpenoid CDDO as a novel therapy for resistant breast cancer," Proc. Amer. Assoc. Cancer Res., 44:2726, 2003.
190 Konopleva et al., "The novel triterpenoid CDDO-Me suppresses MAPK pathways and promotes p38 activation in acute myeloid leukemia cells," Leukemia, 19:1350-1354, 2005.
191 Konopleva et al., "The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces caspase-dependent and -independent apoptosis in acute myelogenous leukemia," Cancer Res., 64:7927-7935, 2004.
192 Konopleva et al., "Triterpenoid Methyl-CDDO Is a Potent Inducer of Apoptosis in CD34+ AML Progenitor Cells Via Activation of SAPK Pathways and Inhibition of MAPK Cascades," Blood, 104:2533, 2004.
193 Kornblau et al., "Apoptosis regulating proteins as targets of therapy for hematological malignancies," Exp. Opin. Inv. Drugs, 8:2027-2057, 1999.
194 Kornblau et al., "Phase I study of mitoxantrone plus etoposide with multidrug blockage by SDZ PSC-833 in relapsed or refractory acute myelogenous leukemia," J. Clin. Oncol., 15(5):1796-1802, 1997.
195 Kowalski and Reddy, "Ester homologation revisited: a reliable, higher yielding and better understood procedure," J. Org. Chem., 57:7194-7208, 1992.
196 Kress et al., "Triterpenoids Display Single Agent Activity in a Mouse Model of CLL/SBL," Blood, 108(11):2530, 2006.
197 Kress et al., "Triterpenoids Display Single Agent Anti-tumor Activity in a Transgenic Mouse Model of Chronic Lymphocytic Leukemia and Small B Cell Lymphoma," PLoS ONE, 6(e559):1-11, 2007.
198 Kruger et al., "Up-regulation of heme oxygenase provides vascular protection in an animal model of diabetes through its antioxidant and antiapoptotic effects," J. Pharmacol. Exp. Ther.,319 (3): 1144-1152, 2006.
199 Kumar and Seshadri, "Triterpenoids of Pterocarpus santalinus: constitution of a new lupene diol," Phytochemistry, 14 (2): 521-523, 1975.
200 Kundu et al., "Synthese von 2α-methoxycarbonyl-A-nor-lupa," Chemische Beerichte, 101 (9): 3255-3264, 1968. (German only, but see attached English CAPLUS database summary.).
201 Kurbacher et al., "Ascorbic acid (vitamin C) improves the antineoplastic activity of doxorubicin, cisplatin, and paclitaxel in human breast carcinoma cells in vitro," Cancer Lett., 103:183-189, 1996.
202 Kurinna et al., "The novel triterpenoid CDDO-Me promotes apoptosis in Gleevec-resistant chronic myeloid leukemia cells by caspase-independent mechanisms," Proc. Amer. Assoc. Cancer Res., 46:2240, 2005.
203 Lala et al., "Role of nitric oxide in tumor progression: lessons from experimental tumors," Cancer and Metastasis Reviews, 17 (1): 91-106, 1998.
204 Langille et al., "Differential effects of physiological concentrations of retinoic acid in vitro on chondrogenesis and myogenesis in chick craniofacial mesenchyme," Differentiation, 40:84, 1989.
205 Lapillonne et al., "Activation of peroxisome proliferator-activated receptor gamma by a novel synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces growth arrest and apoptosis in breast cancer cells," Cancer Res., 63:5926-5939, 2003.
206 Lavie and Shvo, "Constituents of Ecballium elaterium: proposed structure for elatericin A and B," Chemistry and Industry, (London, United Kingdom), 429-430, 1959.
207 Lawrie et al. "Isolation of derivatives of ursolic acid from apple skin," Chemistry and Industry, (London, United Kingdom), 41: 1720, 1966.
208 Lawson et al., "Isolation and preliminary characterization of a monoclonal antibody that interacts preferentially with the liver isoenzyme of human alkaline phosphatase," Clin. Chem., 31:381-385, 1985.
209 Lee et al., "Functional and quantitative analysis of splenic T cell immune responses following oral toxoplasma gondii infection in mice, " Experimental Parasitology, 91:212-221, 1999.
210 Lehn and Ourisson, "Nuclear magnetic response (N.M.R.) of natural products. I. General introduction. Triterpenes of the lupane series. Methyl groups," Bulletin de la Societe Chimique de France, 1137-1142, 1962. (French only, but see attached English CAPLUS database summary.).
211 Lehn and Ourisson, "Syntheses in the lupane series," Bulletin de la Societe Chimque de France, 1133-1136, 1962. (French only, but see attached English CAPLUS database summary.).
212 Lehn and Vystreil, "Resonance magnetique nucleaire de produits naturels—VI : Triterpènes dérivés de la bétuline," Tetrahedron, 19 (11): 1733-1745, 1963. (English abstract).
213 Lemieux, "Acylglycosyl Halides. [55] tetra-O-acetyl-alpha-D-glucopyranosyl bromide," Methods Carbohydr. Chem., 2:221-222, 1963.
214 Lemieux, "Acylglycosyl Halides. [55] tetra-O-acetyl-α-D-glucopyranosyl bromide," Methods Carbohydr. Chem., 2:221-222, 1963.
215 Leonard et al., "Expression of nitric oxide synthase in inflammatory bowel disease is not affected by corticosteroid treatment," J. Clin. Pathol., 51:750-753, 1998.
216 Li and Nel, "Role of the Nrf2-mediated signaling pathway as a negative regulator of inflammation: implications for the impact of particulate pollutants on asthma," Antioxidants & Redox Signaling, 8:88-98, 2006.
217 Li et al., "Studies on constituents of Rosa multiflora thunb," Zhongguo Yaoke Daxue Xuebao, 33 (3): 184-187, 2002. (Chinese only, but see attac hed English CAPLUS database summary.).
218 Liby et al., "A novel acetylenic tricyclic bis-(cyano enone) potently induces phase 2 cytoprotective pathways and blocks liver carcinogenesis induced by aflatoxin," Cancer Res., 68:6727-6733, 2008.
219 Liby et al., "The rexinoid LG100268 and the synthetic triterpenoid CDDO-methyl amide are more potent than erlotinib for prevention of mouse lung carcinogenesis," Mol. Cancer Ther., 7:12-51-1257, 2008.
220 Liby et al., "The synthetic triterpenoids, CDDO and CDDO-imidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE signaling," Cancer Res., 65:4789-4798, 2005.
221 Liby et al., "Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer," Nature Reviews Cancer, 7:357-369, 2007.
222 Lieu et al., "Dual cytotoxic mechanisms of submicromolar taxol on human leukemia HL-60 cells," Biochem. Pharmacology, 53:1587-1596, 1997.
223 Ling et al., "The novel triterpenoid C-28 methyl ester of 2-cyano-3, 12-dioxoolen-1, 9-dien-28-oic acid inhibits metastatic murine breast tumor growth through inactivation of STAT3 signaling," Cancer Res., 67:4210-4218, 2007.
224 Ling et al., "The novel triterpenoid CDDO-Me inhibits metastatic murine breast tumor through inhibition of Stat3 signaling," 2007 AACR Annual Meeting, Abstract No. 301, 2007.
225 Liotta et al., "A simple method for the efficient sysnthesis of unsaturated ∃-dicarbonyl compunds," J. Org. Chem., 46:2920-2923, 1981.
226 Liu et al., "Heme oxygenase-1 (HO-1) inhibits postmyocardial infarct remodeling and restores ventricular function," FASEB J., 20 (2): 207-216, 2006.
227 Long, "Regulation of human bone marrow-derived osteoprogenitor cells by osteogenic growth factors ," Clin. Invest., 95:881-887, 1995.
228 Lugemwa et al., "A heliothis zea antifeedant from the abundant birchbark triterpene betulin", Journal of Agricultural and Food Chemistry, 38 (2): 493-496, 1990.
229 Luo et al., "IKK/NF-kappaB signaling: balancing life and death—a new approach to cancer therapy," J. Clin. Invest., 115 (10): 2625-2631, 2005.
230 MacMicking et al., "Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase," Cell, 81:641-650, 1995.
231 Mane and Ingle, "Synthesis and biological activity of some new 1,5-benzothiazepines containing thiazole moiety: 2-aryl-4-(4-methyl -2-substituted-aminothiazol-5-yl)-2,3-dihydro-1, 5-benzothiazepines," Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 21B (10): 973-974, 1982.
232 Mantovani, "Inflammation by remote control," Nature, 435:752-753, 2005.
233 Manzoor-i-Khuda and Habermehl, "Chemical constituents of Corchorus capsularis and C. olitorium (jute plant). III. Structure of corosin," Zeitschrifi fuer Naturforschung, Teil C: Biochemie, Biophysik, Biologie, Virologie, 29 (5-6): 209-221, 1974.
234 Manzoor-i-Khuda, "Isolation techniques for active principles from plants and their composition and structure determination through spectroscopic techniques," New Trends Nat. Prod., 26: 303-323, 1986.
235 Marnett, "Aspirin and the potential role of prostaglandins in colon cancer," Cancer Res., 52(20):5575-5589, 1992.
236 Marrogi et al., "Nitric oxide synthase, cyclooxygenase 2, and vascular endothelial growth factor in the angiogenesis of non-small cell lung carcinoma," Clinical Cancer Research, 6:4739-4744, 2000.
237 Maurel et al., "Phase I trial of weekly gemcitabine at 3-h infusion in refractory, heavily pretreated advanced solid tumors," Anti-Cancer Drugs, 12 (9): 713-717, 2001.
238 McGeer and McGeer, "The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases," Brain Research Reviews, 21:195-218, 1995.
239 Mehta et al., "Activation of retinoid receptors RAR alpha and RXR alpha induces differentiation and apoptosis, respectively, in HL-60 cells," Cell, Growth Differ, 7(2): 179-186, 1996.
240 Melichar et al., "Growth-inhibitory effect of a novel synthetic triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, on ovarian carcinoma cell lines not dependent on peroxisome proliferator-activated receptor-gamma expression," Gynecologic Oncology, 93:149-154, 2004.
241 Mella et al., "1, 2-dideoxy-3, 4:5, 7-bis-o—(1-methylethylidene)—D-gluco- and -D-galacto-hept-1-ynitols : synthesis and conformational studies, " Tetrahedron, 44:1673-1678, 1988.
242 Mella et al., "1, 2-dideoxy-3, 4:5, 7-bis-o—(1-methylethylidene)—D-gluco- and -D-galacto-hept-1-ynitols : synthesis and conformational studies," Tetrahedron, 44:1673-1678, 1988.
243 Merril and Benveniste, "Cytokines in inflammatory brain lesions: helpful and harmful," Trends Neurosci., 19:331-338, 1996.
244 Minns et al., "A novel triterpenoid induces transforming growth factor beta production by intraepithelial lymphocytes to prevent ileitis," Gastroenterology, 127:119-126, 2004.
245 Misra et al., "Studies on autoxidation: Part II—synthesis of isomeric 2,3-diols of Δ12-oleanene," Indian J. of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 14B (6): 411-414, 1976.
246 Mix et al., "A synthetic triterpenoid selectively inhibits the induction of matrix metalloproteinases 1 and 13 by inflammmatory cytokines," Arthritis Rheum., 44:1096-1104, 2001.
247 Mix et al., "Peroxisome proliferator-activated receptor-gamma-independent repression of collagenase gene expression by 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid and prostaglandin 15-deoxy-delta(12,14) J2: a role for Smad signaling," Mol. Pharmacol., 65:309-318, 2004.
248 Moncada et al., "Nitric oxide: physiology, pathophysiology, and pharmacology," Pharmacol. Rev., 43:109-142, 1991.
249 Morris et al., "Association of a functional inducible nitric oxide synthase promoter variant with complications in type 2 diabetes," J. Mol. Med., 80 (2): 96-104, 2002.
250 Morse and Choi, "Heme oxygenase-1: from bench to bedside," Am. J. Respir. Crit. Care Med., 172 (6): 660-670, 2005.
251 Morse and Choi, "Heme oxygenase-1: the ‘emerging molecule’ has arrived," Am. J. Respir. Crit. Care Med., 27(1):8-16, 2002.
252 Murphy et al., "Immunomodulatory Effects of the Triterpenoid CDDO after Allogeneic Bone Marrow Transplantation in Mice: Reduction of Acute Graft-Versus-Host Disease Lethality," Blood, 106:1316, 2005.
253 Murray and Zweifel, "Preparation of Phenyl Cyanate and Its Utilization for the Synthesis of α, β-Unsaturated Nitriles," Synthesis, 150-151, 1980.
254 Muzart, "Synthesis of unsaturated carbonyl compounds via a chromium-mediated allylic oxidation by 70% tert.butylhydroperoxide," Tetrahedron Lett., 28:4665-4668, 1987.
255 Na and Surh et al., "Transcriptional regulation via cysteine thiol modification: a novel molecular strategy for chemoprevention and cytoprotection," Mol. Carcinog.,45 (6): 368-380, 2006.
256 Nathan and Xie, "Nitric oxide synthases: roles, tolls, and controls," Cell, 78:915-918, 1994.
257 Nathan et al., "Protection from Alzheimer's-like disease in the mouse by genetic ablation of inducible nitric oxide synthase," The Journal of Experimental Medicine, 202:1163-1169, 2005.
258 Nathan, "Points of control in inflammation," Nature, 420:846-852, 2002.
259 Nicholson et al., "Lethality of endotoxin in mice genetically deficient in the respiratory burst oxidase, inducible nitric oxide synthase, or both," Shock, 11:253-258, 1999.
260 Nishino et al., "Inhibition of the tumor-promoting action of 12-O tetradecanoylphorbol-13-acetate by some oleanane-type triterpenoid compounds," Cancer Res., 48:5210-5215, 1988.
261 Notice of Allowance, in U.S. Appl. No. 11/927,418, mailed Mar. 15, 2010.
262 Office Action issued in Canadian Application No. 2,335,505, mailed Jan. 10, 2008.
263 Office Action issued in Canadian Application No. 2,335,505, mailed Nov. 23, 2006.
264 Office Action issued in Canadian Application No. 2,335,505, mailed Sep. 22, 2008.
265 Office Action issued in European Application No. 99 928 731.1, mailed Aug. 1, 2008.
266 Office Action issued in European Application No. 99 928 731.1, mailed Dec. 15, 2004.
267 Office Action issued in European Application No. 99 928 731.1, mailed Feb. 14, 2007.
268 Office Action, in Canadian Patent App. No. 2,335,505, mailed May 4, 2009.
269 Office Action, in Canadian Patent App. No. 2,430,454, mailed Jan. 20, 2009.
270 Office Action, in European Patent App. No. 01 989 130, mailed Jul. 31, 2008.
271 Office Action, in European Patent App. No. 01 989 130, mailed Mar. 24, 2009.
272 Office Action, in European Patent App. No. 03 729 681, mailed Nov. 6, 2008.
273 Office Action, in U.S. Appl. No. 09/335,003, mailed Aug. 28, 2000.
274 Office Action, in U.S. Appl. No. 09/335,003, mailed Mar. 15, 2001.
275 Office Action, in U.S. Appl. No. 09/335,003, mailed Nov. 2, 2000.
276 Office Action, in U.S. Appl. No. 09/927,081, mailed Feb. 22, 2002.
277 Office Action, in U.S. Appl. No. 09/998,009, mailed Apr. 4, 2007.
278 Office Action, in U.S. Appl. No. 09/998,009, mailed Jul. 11, 2005.
279 Office Action, in U.S. Appl. No. 09/998,009, mailed Jul. 14, 2004.
280 Office Action, in U.S. Appl. No. 09/998,009, mailed Mar. 24, 2004.
281 Office Action, in U.S. Appl. No. 09/998,009, mailed Nov. 16, 2007.
282 Office Action, in U.S. Appl. No. 09/998,009, mailed Nov. 30, 2005.
283 Office Action, in U.S. Appl. No. 09/998,009, mailed Oct. 20, 2004.
284 Office Action, in U.S. Appl. No. 10/345,053, mailed Aug. 25, 2004.
285 Office Action, in U.S. Appl. No. 10/345,053, mailed Dec. 23, 2004.
286 Office Action, in U.S. Appl. No. 10/345,053, mailed Dec. 6, 2005.
287 Office Action, in U.S. Appl. No. 10/345,053, mailed Mar. 1, 2006.
288 Office Action, in U.S. Appl. No. 10/345,053, mailed May 31, 2005.
289 Office Action, in U.S. Appl. No. 10/395,372, mailed Apr. 28, 2006.
290 Office Action, in U.S. Appl. No. 10/395,372, mailed Aug. 4, 2005.
291 Office Action, in U.S. Appl. No. 10/395,372, mailed Dec. 20, 2006.
292 Office Action, in U.S. Appl. No. 10/395,372, mailed Feb. 7, 2007.
293 Office Action, in U.S. Appl. No. 10/395,372, mailed Jan. 28, 2004.
294 Office Action, in U.S. Appl. No. 10/395,372, mailed Jul. 9, 2004.
295 Office Action, in U.S. Appl. No. 10/395,372, mailed Jun. 12, 2006.
296 Office Action, in U.S. Appl. No. 10/395,372, mailed May 23, 2005.
297 Office Action, in U.S. Appl. No. 10/395,372, mailed Nov. 23, 2005.
298 Office Action, in U.S. Appl. No. 10/435,925, mailed Sep. 30, 2005.
299 Office Action, in U.S. Appl. No. 11/672,449, mailed Jun. 13, 2008.
300 Office Action, in U.S. Appl. No. 11/672,449, mailed Mar. 20, 2009.
301 Office Action, in U.S. Appl. No. 11/927,418, mailed Mar. 2, 2009.
302 Office Action, in U:S. Appl. No. 09/998,009, mailed Jul. 3, 2006.
303 Ohshima and Bartsch, "Chronic infections and inflammatory process as cancer risk factors: possible role of nitric oxide in carcinogenesis," Mutat. Res., 305:253-264, 1994.
304 Omura and Swern, "Oxidation of Alcohols by ‘Activated’ Dimethyl Sulfoxide. A Preparative Steric and Mechanistic Study," Tetrahedron, 34:1651-1660, 1978.
305 Ono et al., "A convenient procedure for esterification of carboxylic acids," Bull. Chem. Soc. Jpn., 51:2401-2404, 1978.
306 Osburn et al., "Genetic of pharmacologic amplification of Nrf2 signaling inhibits acute inflammatory liver injury in mice," Toxicological Sciences, 104:218-227, 2008.
307 Oshima et al., "Suppression of intestinal polyposis in ApcDelta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2)," Cell, 87:803-809, 1996.
308 Oshima et al., "Suppression of intestinal polyposis in ApcΔ716 knockout mice by inhibition of cyclooxygenase 2 (COX-2)," Cell, 87:803-809, 1996.
309 Osman et al., "Application of chemical reactions on thin-layer chromatoplates. IV. Triterpene," Bulletin of the Chemical Society of Japan, 47 (8): 2056-2058, 1974.
310 Osman et al., "Chemical studies on pentacyclic triterpenes. I. Benzilic acid rearrangement of ring A in ursolic acid," Egyptian J. of Chemistry, 15 (3): 269-272, 1972.
311 Pahl, "Activators and target genes of Rel/NF-κB transcription factors," Oncogene, 18:6853-6866, 1999.
312 Palcy and Goltzman, "Protein kinase signalling pathways involved in the up-regulation of the rat alpha1 (I) collagen gene by transforming growth factor beta1 and bone morphogenetic protein 2 in osteoblastic cells," Biochem. J., 343:21-27, 1999.
313 Patel et al., "Phase II clinical investigation of gemcitabine in advanced soft tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate accumulation," J. Clin. Oncol., 19 (15): 3483-3489, 2001.
314 Paul et al., "Design and synthesis of a self-assembled photochemical dyad based on selective imidazole recognition," Inorg. Chem., 41:3699-3704, 2002.
315 Paul et al., "Effective expression of small interfering RNA in human cells," Nature Biotechnol., 20:505-508, 2002.
316 PCT, International Preliminary Examination Report, in Int. App. No. PCT/US1999/13635, mailed Sep. 6, 2000.
317 PCT, International Preliminary Examination Report, in Int. App. No. PCT/US2001/44541, mailed Jan. 15, 2004.
318 PCT, International Preliminary Examination Report, in Int. App. No. PCT/US2003/01307, mailed Oct. 20, 2003.
319 PCT, International Search Report, in Int. App. No. PCT/US1999/13635, mailed Oct. 20, 1999.
320 PCT, International Search Report, in Int. App. No. PCT/US2001/44541, mailed Jan. 24, 2003.
321 PCT, International Search Report, in Int. App. No. PCT/US2003/01307, mailed May 12, 2003.
322 PCT, Written Opinion, in Int. App. No. PCT/US1999/13635, mailed May 15, 2000.
323 PCT, Written Opinion, in Int. App. No. PCT/US2001/44541, mailed Sep. 23, 2003.
324 Pedersen et al., "The triterpenoid CDDO induces apoptosis in refractory CLL B cells," Blood, 100:2965-2972, 2002.
325 Petition Decision, issued in U.S. Appl. No. 10/345,053, mailed May 22, 2006.
326 Picard et al., "Structure of the triterpenes," J. Soc. Chem. Ind., 58: 58-59, 1939.
327 Picard et al., "The triterpene resinols and related acids, part VI," J. Chem. Soc., 1045-108, 1939.
328 Pitzele, "Synthesis of 2-oxygenated glycyrrhetic acid derivatives," J. of Medicinal Chemistry, 117 (2): 191-194, 1974.
329 Place et al., "The novel synthetic triterpenoid, CdDDO-imidazolide, inhibits inflammatory response and tumor growth in vivo," Clin. Cancer Res., 9:2798-2806, 2003.
330 Pollard, "Tumour-educated macrophages promote tumour progression and metastasis," Nature Reviews Cancer, 4:71-78, 2004.
331 Pradhan and De, "Preparation of triterpenoid diosphenol via oximinoketone and structure of baccatin," Indian J. of Chemistry, Section B: Organic Chemistry including Medicinal Chemistry, 21B (9): 823-828, 1982.
332 Pradhan and Ghosh, "Studies on reactions of 2-bromo-3-ketotriterpenoids: Part IV. Debromination and dehydrobromination of 2α-bromo and 2,2-dibromo derivatives of lupanone and methyl dihydrobetulonate," Indian J. of Chemistry, Section B: Organic Chemistry including Medicinal Chemistry, 33B (1): 73-75, 1994.
333 Prescott and White, "Self-promotion? Intimate connections between APC and prostaglandin H synthase-2," Cell, 87:783-786, 1996.
334 Rangasamy et al., "Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice," Journal of Experimental Medicine, 202:47-59, 2005.
335 Rayet and Gelinas, "Aberrant rel/nfkb genes and activity in human cancer," Oncogene, 18:6938-6947, 1999.
336 Reddy et al., "Evaluation of cyclooxygenase-2 inhibitor for potential chemopreventive properties in colon carcinogenesis," Cancer Res., 56(20):4566-4569, 1996.
337 Response filed in Canadian Application No. 2,335,505, mailed Jul. 10, 2008.
338 Response filed in Canadian Application No. 2,335,505, mailed May 11, 2007.
339 Response filed in European Application No. 99 928 731.1, mailed Aug. 14, 2007.
340 Response filed in European Application No. 99 928 731.1, mailed Jun. 23, 2005.
341 Response filed in European Application No. 99 928 731.1, mailed Oct. 1, 2008.
342 Response to Office Action, in Canadian Patent App. No. 2,335,505, dated Mar. 23, 2009.
343 Response to Office Action, in European Patent App. No. 01 989 130, dated Sep. 5, 2008.
344 Response to Office Action, in European Patent App. No. 99 928 731, dated Mar. 9, 2009.
345 Response to Office Action, in U.S. Appl. No. 09/335,003, dated Apr. 16, 2001.
346 Response to Office Action, in U.S. Appl. No. 09/335,003, dated Mar. 2, 2001.
347 Response to Office Action, in U.S. Appl. No. 09/335,003, dated Sep. 28, 2000.
348 Response to Office Action, in U.S. Appl. No. 09/927,081, dated Jun. 24, 2002.
349 Response to Office Action, in U.S. Appl. No. 09/998,009, dated Apr. 19, 2005.
350 Response to Office Action, in U.S. Appl. No. 09/998,009, dated Apr. 21, 2004.
351 Response to Office Action, in U.S. Appl. No. 09/998,009, dated Feb. 18, 2008.
352 Response to Office Action, in U.S. Appl. No. 09/998,009, dated Jan. 3, 2007.
353 Response to Office Action, in U.S. Appl. No. 09/998,009, dated Mar. 30, 2006.
354 Response to Office Action, in U.S. Appl. No. 09/998,009, dated Oct. 11, 2005.
355 Response to Office Action, in U.S. Appl. No. 09/998,009, dated Sep. 14, 2004.
356 Response to Office Action, in U.S. Appl. No. 09/998,009, dated Sep. 4, 2007.
357 Response to Office Action, in U.S. Appl. No. 10/345,053, dated Feb. 6, 2006.
358 Response to Office Action, in U.S. Appl. No. 10/345,053, dated Mar. 23, 2005.
359 Response to Office Action, in U.S. Appl. No. 10/345,053, dated Sep. 24, 2004.
360 Response to Office Action, in U.S. Appl. No. 10/345,053, dated Sep. 3, 2005.
361 Response to Office Action, in U.S. Appl. No. 10/395,372, dated Apr. 21, 2006.
362 Response to Office Action, in U.S. Appl. No. 10/395,372, dated Apr. 28, 2004.
363 Response to Office Action, in U.S. Appl. No. 10/395,372, dated Feb. 14, 2007.
364 Response to Office Action, in U.S. Appl. No. 10/395,372, dated Jan. 12, 2007.
365 Response to Office Action, in U.S. Appl. No. 10/395,372, dated Jul. 25, 2005.
366 Response to Office Action, in U.S. Appl. No. 10/395,372, dated Nov. 23, 2005.
367 Response to Office Action, in U.S. Appl. No. 10/395,372, dated Nov. 9, 2004.
368 Response to Office Action, in U.S. Appl. No. 10/395,372, dated Oct. 12, 2006.
369 Response to Office Action, in U.S. Appl. No. 10/435,925, dated Mar. 30, 2005.
370 Response to Office Action, in U.S. Appl. No. 11/672,449, dated Dec. 15, 2008.
371 Response to Office Action, in U.S. Appl. No. 11/927,418, dated Apr. 2, 2009.
372 Response to Written Opinion, in Int. App. No. PCT/US1999/13635, dated Jul. 14, 2000.
373 Richardson et al., "Synthesis and restriction enzyme analysis of oligodeoxyribonucleotides containing the anti-cancer drug 2′,2′-difluoro-2′-deoxycytidine," Nucleic Acid Res., 20 (7): 1763-1769, 1992.
374 Rizzieri et al., "Phase I evaluation of prolonged-infusion gemcitabine with mitoxantrone for relapsed or refractory acute leukemia," J. Clin. Oncol., 20 (3): 674-679, 2002.
375 Robbins et al., "Inflammation and Repair," In: Basic Pathology 3rd Edition, W.B. Saunders Company, Chapter 2, p. 28, 1981.
376 Rossi et al., "Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase," Nature, 403:103-108, 2000.
377 Ruvolo et al., "The novel triterpenoid methyl-CDDO inhibits Bc12 phosphorylation and potently kolls U937 cells," Blood, 94(10), Suppl. 1, Part 1: 280A, abstract #1251, 1999.
378 Sacerdoti et al., "Heme oxygenase overexpression attenuates glucose-mediated oxidative stress in quiescent cell phase: linking heme to hyperglycemia complications," Curr. Neurovasc. Res., 2(2): 103-111, 2005.
379 Salvemini et al., "Endogenous nitric oxide enhances prostaglandin production in a model of renal inflammation," J. Clin. Invest., 93(5):1940-1947, 1994.
380 Salvemini et al., "Nitric oxide activates cyclooxygenase enzymes," Proc. Natl. Acad. Sci. USA, 90(15):7240-7244, 1993.
381 Samudio et al., "2,cyano-3,12 dioxoolean-1,9 diene-28-imidazolide induces apoptosis in pancreatic cancer via redox-dependent cytoplasmic stress," Proc. Amer. Assoc. Cancer Res., 46:5899, 2005.
382 Samudio et al., "2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) directly targets mitochondrial glutathione to induce apoptosis in pancreatic cancer," J. Biol. Chem., 280:36273-36282, 2005.
383 Samudio et al., "A Novel Mechanism of Action of Methyl-2-cyano-3,12 dioxoolean-1,9 diene-28-oate (CDDO-Me): Direct Permeabilization of the Inner Mitochondrial Membrane to Inhibit Electron Transport and Induce Apoptosis," Blood, 106:4462, 2005.
384 Samudio et al., "A novel mechanism of action of methyl-2-cyano-3,12 dioxoolean-1,9 diene-28-oate (CDDO-Me): Direct permeabilization of the inner mitochondrial membrane to inhibit electron transport and induce apoptosis," Proc. Am. Assoc. Cancer Res., 47: 4693, 2006.
385 Samudio et al., "A novel mechanism of action of methyl-2-cyano-3,12 dioxoolean-1,9 diene-28-oate: direct permeabilization of the inner mitochondrial membrane to inhibit electron transport and induce apoptosis," Mol. Pharmacol., 69:1182-1193, 2006.
386 Samudio et al., "The novel triterpenoid CDDOme potently synergizes with inhibition of bcl-2 function to induce apoptosis in AML via disruption of intracellular redox homeostasis," Proc. Amer. Assoc. Cancer Res., 46:4955, 2005.
387 Satoh et al., "Activation of the Keap1/Nrf2 pathway for neuroprotection by electrophilic [correction of electrophillic] phase II inducers," PNAS, 103 (3): 768-773, 2006.
388 Scholz et al., "Sensitive and specific methods for the determination of CDDO methyl ester in mouse, rat, dog, monkey, and human plasma by LC-tandem mass spectrometry," Proc. Amer. Assoc. Cancer Res., 4:6321, 2003.
389 Seibert and Masferrer, "Role of inducible cyclooxygenase (COX-2) in inflammation," Receptor, 4(1):17-23, 1994.
390 Sejbal et al., "Triterpenes. Part LXXIII. Reactions of triterpenoid ketones with sulfur and morpholine under Willgerodt-Kindler reaction conditions," Collection of Czechoslovak Chemical Communications, 51 (1): 118-127, 1986.
391 Sejbal et al., "Triterpenes. Part XC. Conversion of betulin into careyagenolide (2α,3β-dihydroxy-18α, 19βH-ursan-28, 20β-olide," Collection of Czechoslovak Chemical Communications, 54 (4): 1036-1042, 1989.
392 Sharpless et al., "Electrophilic and nucleophilic organoselenium reagents. New routes to alpha, beta-unsaturated carbonyl compounds," J. Am. Chem. Soc., 95:6137, 1973.
393 Sheng et al., "A selective cyclooxygenase 2 inhibitor suppresses the growth of H-ras-transformed rat intestinal epithelial cells," Gastroenterology, 113(6):1883-18891, 1997.
394 Sheng et al., "Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2," J. Clin. Invest., 99(9):2254-2259, 1997.
395 Shimao and Oae, "Activity coefficients of dimethyl-β-cyclodextrin in aqueous solution," Bulletin of the Chemical Society of Japan, 56 (2): 643-644, 1983.
396 Shishodia et al., "A synthetic triterpenoid, CDDO-Me, inhibits IkappaBalpha kinase and enhances apoptosis induced by TNF and chemotherapeutic agents through down-regulation of expression of nuclear factor kappaB-regulated gene products in human leukemic cells," Clin. Cancer Res., 12:1828-1838, 2006.
397 Shull et al., "Identification of a vitamin D-responsive protein on the surface of human osteosarcoma cells," Proc. Natl. Acad. Sci. USA, 86:5405-5410, 1989.
398 Shull et al., "Morphologic and Biochemical Studies of Canine Mucopolysaccharidosis I," Am. J. Pathol., 114:487-495, 1984.
399 Simonian and Coyle, "Oxidative stress in neurodegenerative diseases," Annu. Rev. Pharmacol. Toxicol., 36:83-106, 1996.
400 Simonsen et al., "Tetracyclic hydroxy acids," In the Terpenes, Cambridge University, Cambridge, 5:221-285, 1957.
401 Singh and Evans, "Nitric oxide, the biological mediator of the decade: fact or fiction?" Eur. Respir. J., 10:699-707, 1997.
402 Singh et al., "Anti-inflammatory activity of oleanolic acid in rats and mice," J. Pharm.Pharmacol., 44:456-458, 1992.
403 Sive et al., "Expression of chondrocyte markers by cells of normal and degenerate intervertebral discs," Mol. Pathol., 55:91-97, 2002.
404 Snitman et al., "Synthetic approaches to taxodione synthesis of methyl 12-oxopodocarpa-5,9(11)-diene-8β-carboxylate," Synth. Comm., 8:187-194, 1978.
405 Sonogashira et al., "A convenient synthesis of acetylenes: catalytic substitutions of acetylenic hydrogen with bromoakenes, iodoarenes, and bromopyridines," Tetrahedron Lett., 4467-4470, 1975.
406 Sporn and Roberts, "Peptide growth factors and inflammation, tissue repair, and cancer," J. Clin. Invest., 78:329-332, 1986.
407 Sporn et al., "Prospects for prevention and treatment of cancer with selective PPARγ modulators (SPARMs)," Trends in Molecular Medicine, 7(9):395-400, 2001.
408 Sporn et al., "Transforming Growth Factor-β: Biological Function and Chemical Structure," Science, 233:532-534, 1986.
409 Stadheim et al., "The novel triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) potently enhances apoptosis induced by tumor necrosis factor in human leukemia cells," J. Biol. Chem., 277:16448-16455, 2002.
410 Steadman's Medical Journal 23rd Edition, The Williams & Wilkins Company, p. 401, 1976.
411 Sterzycki, "Pyrodinium tosylate, a mild catalyst for formation and cleavage of dioxolane-type acetals," Synthesis, 724-725, 1979.
412 Stewart et al., "Risk of Alzheimer's disease and duration of NSAID use" Neurology, 48:626-632, 1997.
413 Strejan et al., "Suppression of chronic-relapsing experimental allergic encephalomyelitis in strain-13 guinea pigs by administration of liposome-associated myelin basic protein," J. Neuroimmunol., 7 (1): 27, 1984.
414 Suh et al., "A novel synthetic oleanane triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), induces cell differentiation in human myeloid leukemias," Proceedings of the American Association for Cancer Research Annual Meeting, 40:300, abstract # 1988, 1999.
415 Suh et al., "A novel synthetic oleanane triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, with potent differentiating, antiproliferative, and anti-inflammatory activity," Cancer Res., 59(2):336-341, 1999.
416 Suh et al., "New triterpenoids as cancer preventive and anti-inflammatory agents," 88th AACR Meeting, San Francisco, California, abstract No. 1457, Mar. 1997.
417 Suh et al., "New triterpenoids as cancer preventive and anti-inflammatory agents," 88th AACR Meeting, San Francisco, California, poster, Mar. 1997.
418 Suh et al., "New triterpenoids as cancer preventive and anti-inflammatory agents," Proceedings of the American Association for Cancer Research, Abstract No. 1457, 38: 216, 1997.
419 Suh et al., "Novel triterpenoids suppress inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2) in mouse macrophages," Cancer Res., 58:717-723, 1998.
420 Suh et al., "Novel triterpenoids suppress inducible nitric oxide synthase (INOS) and inducible cyclooxygenase (COX-2)," 89th AACR Meeting, New Orleans, Louisiana, slides from oral presentation, Mar. 28-Apr. 1, 1998.
421 Suh et al., "Novel triterpenoids suppress inducible ntiric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2)," Proceedings of the American Association for Cancer Research Annual Meeting, 39:266, 1998.
422 Suh et al., "Synthetic triterpenoids activate a pathway for apoptosis in AML cells involving downregulation of Flip and sensitization to Trail," Leukemia, 17:2122-2129, 2003.
423 Suh et al., "Synthetic triterpenoids enhance transforming growth factor β/Smad signaling," Cancer Res., 63:1371-1376, 2003.
424 Suh et al., "Triterpenoids CDDO and CDDO-Me Down-Regulate Flip Expression and Sensitize AML Cells to Trail-Induced Apoptosis," American Society of Hematology 43rd Annual Meeting and Exposition, Abstract No. 498, 2001.
425 Sun et al., "The synthetic triterpenoid, CDDO, suppresses alloreactive T cell responses and reduces murine early acute graft-versus-host disease mortality," Biology of Blood and Marrow Transplantation, 13:521-529, 2007.
426 Supplementary European Search Report, issued in European Patent App. No. 01 989 130, mailed Aug. 9, 2007.
427 Supplementary European Search Report, issued in European Patent App. No. 03 729 681, mailed Aug. 3, 2006.
428 Syftestad et al., "The in vitro chondrogenic response of limb-bud mesenchyme to a water-soluble fraction prepared from demineralized bone matrix," Differentiation, 29:230, 1985.
429 Tabe et al., "Chrmoatin-Mediated Transcriptional Activation with Novel Peroxisome Proliferator—Activated Receptor gamma(PPARgamma) Ligand 2-cyano-1,9-dien-28-oic Acid (CDDO) in Acute Promyelocytic Leukemia Cells," Abstracts of the 44th Annual Meeting of the American Society of Hematology, Abstract No. 2191, 2002.
430 Takabe et al., "Synthesis of lycosyl esters of oleanolic," Carbohydrate Research, 76:101-108, 1979, Database CAPLUS on STN AN:1980:42278.
431 Takahashi et al., "Increased expression of inducible and endothelial constitutive nitric oxide synthases in rat colon tumors induced by azoxymethane," Cancer Res., 57:1233-1237, 1997.
432 Tamir and Tannebaum, "The role of nitric oxide (NO) in the carcinogenic process," Biochim. Biophys. Acta, 1288:F31-F36, 1996.
433 Tamm et al., "Expression and prognostic significance of IAP-family genes in human cancers and leukemias," Blood, 94(Suppl. 1):69a, Abstract # 298, 1999.
434 Tempero et al., "Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma," J. Clin. Oncol., 21 (18): 3402-3408, 2003.
435 Tenenbaum and Heersche, "Differentiation of Osteoblasts and Formation of Mineralized Bone in Vitro," Calcif. Tissue Int., 34:76, 1982.
436 Therasse et al., "New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada," J. Natl. Cancer Instit., 92 (3): 205, 2000.
437 Thimmulappa et al., "Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis," J. Clinical Investigation, 116 (4): 984-995, 2006.
438 Thimmulappa et al., "Nrf2-dependent protection from LPS induced inflammatory response and mortality by CDDO-imidazolide," Biochem. Biophys. Res. Commun., 351:883-889, 2006.
439 Thimmulappa et al., "Preclinical evaluation of targeting the Nrf2 pathway by triterpenoids (CDDO-Im and CDDO-Me) for protection from LPS-induced inflammatory response and reactive oxygen species in human peripheral blood mononuclear cells and neutrophils," Antioxidants & Redox Signaling, 9:1-8, 2007.
440 Toriumi et al., "Mandibular Reconstruction With a Recombinant Bone-Inducing Factor: Functional, Histologic, and Biomechanical Evaluation," Arch. Otolaryngol. Head Neck Surg., 117:1101-1112, 1991.
441 Torres et al., "Inflammation and nitric oxide production in skeletal muscle of type 2 diabetic patients," Journal of Endocrinology, 181:419-427, 2004.
442 Tran et al., "The synthetic triterpenoid CDDO-methyl ester modulates microglial activities, inhibits TNF production, and provides dopaminergic neuroprotection," Journal of Neuroinflammation, 5:1-14, 2008.
443 Tsai et al., "Monoclonal Antibody to Human Osteosarcoma: a Novel Mr 26,000 Protein Recognized by Murine Hybridoma TMMR-2," Cancer Res., 50:152-161, 1990.
444 Tsao et al., "DRIP205 co-activator overexpression enhances PPARgamma-mediated differentiation of leukemia cells by CDDO," Proc. Amer. Assoc. Cancer Res., 46:1855, 2005.
445 Tsao et al., "Targeted Induction of Apoptosis in Leukemias by PPARgammma Ligation," American Society of Hematology 43rd Annual Meeting and Exposition, Abstract No. 2381, 2001.
446 Tsujii and DuBois, "Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2," Cell, 83:493-501, 1995.
447 Tsujii et al., "Cyclooxygenases regulates angiogenesis induced by colon cancer cells," Cell, 93:705-716, 1998.
448 Turksen et al., "Isolation of Monoclonal Antibodies Recognizing Rat Bone-Associated Molecules In Vitro and In Vivo," J. Histochem. Cytochem., 40:1339-1352, 1992.
449 U.S. Appl. No. 60/955,939, filed Aug. 15, 2007.
450 U.S. Appl. No. 61/152,608, filed Feb. 13, 2009. (Foley 086836-0110).
451 van Muiswinkel et al., "The Nrf2-ARE signalling pathway: promising drug target to combat oxidative stress in neurodegenetative disorders," Current Drug Target, 4:267-281, 2005.
452 Vazquez et al., "Human immunodeficiency virus type 1-induced macrophage gene expression includes the p21 gene, a target for viral regulation," J. Virol., 79:4479-4491, 2005.
453 Veerman et al., "Antitumor activity of prolonged as compared with bolus administration of 2′,2′-difluorodeoxycytidine in vivo against murine colon tumors," Cancer Chemother. Pharmacol., 38 (4): 335-342, 1996.
454 Vodovotz et al., "Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer's Disease," The Journal of Experimental Medicine, 184:1425-1433, 1996.
455 Vukicevic et al., "Stimulation of the expression of osteogenic and chondrogenic phenotypes in vitro by osteogenin," Proc. Natl. Acad. Sci. USA, 86:8793-7, 1989.
456 Walczak et al., "Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo", Nature Medicine, 5(2):157-163, 1999.
457 Walsh et al., "Monoclonal antibodies with selective reactivity against osteoblasts and osteocytes in human bone," J. Bone Miner Res., 9:1687-1696, 1994.
458 Wang et al., "A novel synthetic triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) induces adipocyte differentiation in 3T3-L1 cells," Proceedings of the American Association for Cancer Research Annual Meeting, 40:300, abstract # 1989, 1999.
459 Wang et al., "A synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), is a ligand for the peroxisome proliferator-activated receptor γ," Mol. Endocrinol., 14:1550-1556, 2000.
460 Wang et al., "Synthetic triterpenoid CDDO and its derivatives increase ceramides and are cytotoxic to pediatric acute lymphoblastic leukemia cell lines," Proc. Am. Assoc. Cancer Res., 47: 4643, 2006.
461 Warrell et al., "Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid)," N. Engl. J. Med., 324(20):1385-1393, 1991.
462 Williams et al., "Immunology of multiple sclerosis," Clin. Neurosci., 2(3-4):229-245, 1994.
463 Williams et al., "Immunology of multiple sclerosis," Clin. Neurosci., 2(3-4):229--245, 1994.
464 Witz et al., "Cyclic ketones. XIII. Circular dichroism of steroid and triterpene ketones. Conformation of ring A of 8-methylated 3-oxotriterpenes," Bull. Soc. China, France: 1101-1112, 1963. (French only, but see attached English CAPLUS database summary.).
465 Woodley, "Liposomes for oral administration of drugs," Critical Reviews in Therapeutic Drug Carrier System,2:1-18, 1995.
466 Xie et al., "Differential expression patterns in human myeloblastic leukemia HL-60 and multidrug resistant HL-60/Dox cells analyzed by human cDNA expression array," Blood, 92 (Suppl 1):387a, Abstract #1600. 1998.
467 Yates et al., "Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes," Mol. Cancer Ther., 6:154-162, 2007.
468 Yates et al., "Potent protection against aflatoxin-induced tumorigenesis through induction of Nrf2-regulated pathways by the triterpenoid 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole," Cancer Res., 66:2488-2494, 2006.
469 Yore et al., "The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole blocks nuclear factor-kappaB activation through direct inhibition of IkappaB kinase beta," Mol. Cancer Ther., 5 (12): 3232-3239, 2006.
470 Yu and Kensler, "Nrf2 as a target for cancer chemoprevention," Mutat. Res., 591 (1-2): 93-102, 2005.
471 Yue et al., "Depletion of intracellular glutathione contributes to JNK-mediated death receptor 5 upregulation and apoptosis induction by the novel synthetic triterpenoid methyl-2-cyano-3, 12-dioxooleana-1, 9-dien-28-oate (CDDO-Me).," Cancer & Biology Therapy, 5(5):492-497, 2006.
472 Yue et al., "Depletion of intracellular glutathione contributes to JNK-mediated death receptor 5 upregulation and apoptosis induction by the novel synthetic triterpenoid methyl-2-cyano-3, 12-dioxooleans-1, 9-dien-28-oate (CDDO-Me).," Cancer & Biology Therapy, 5(5):492-497, 2006.
473 Zapata et al., "CDDO and CDDO-Im Reduce Tumor Burden in a Transgenic Mouse Model of CLL," Blood, 104:3477, 2004.
474 Zapata et al., "Triterpenoids show activity against leukemic cells in a transgenic mouse model of CLL," Proc. Amer. Assoc. Cancer Res., 46:5179, 2005.
475 Zhang et al., "Synthetic triterpenoid CDDO as effective therapy for HER2-expressing resistant breast cancer," Proc. Amer. Assoc. Cancer Res., Abstract No. 3799, 2004.
476 Zhang et al., "The novel synthetic oleanane triterpenoid CDDO (2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid) induces apoptosis in Mycosis fungoides/Sézary syndrome cells," J. Invest. Dermatol., 123:380-387, 2004.
477 Zhou et al., "Carbon monoxide suppresses bleomycin-induced lung fibrosis," Am. J. Pathol., 166 (1): 27-37, 2005.
478 Zhou et al., "Physical stability of amorphous pharmaceuticals: Importance of configurational thermodynamic quantities and molecular mobility," J. Pharmaceutical Sciences, 91 (8): 1863-1872, 2002.
479 Zou et al., "c-Jun NH2-terminal kinase-mediated up-regulation of death receptor 5 contributes to induction of apoptosis by the novel synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1, 9-dien-28-oate in human lung cancer cells," Cancer Res., 64:7570-7578, 2004.
US20100190735 * Apr 1, 2010 Jul 29, 2010 Myrex Pharmaceuticals Inc. Mouthwash and Method of Using Same for the Treatment of Mucositis or Stomatitis
U.S. Classification 514/521, 558/423, 514/463, 558/415, 514/519, 514/522, 514/520
International Classification A61K31/35, C07C255/03, A61K31/275, A61P25/16, C07J63/00, A61P1/04, A61P19/02, A61P21/04, A61P29/00, A61K31/19, A61K31/56, A61K31/277, A61P25/00, A61P35/00, A61P25/28
Cooperative Classification A61K31/35, A61K31/277, A61K31/19, A61K31/275, C07C255/47
European Classification A61K31/275, A61K31/35, A61K31/19, A61K31/277
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