Patent Publication Number: US-2013237511-A1

Title: Copper Ion Delivery Platform for Pharmaceutical Agents

Description:
The inventor of this patent application is not an employee of the United States Government. 
     BACKGROUND OF THE INVENTION 
     1. Field of Invention 
     The present invention relates to a method to increase the efficacy of any pharmaceutical compound that contains a nitrogen atom. Binding a copper ion to a pharmaceutical agent that contains a nitrogen atom can increase its water solubility, its stability and rigidity, and block the nitrogen atom from binding unwanted targets in a physiologically environment. The controlled delivery of pharmaceutical agents to a disease site or cell is a significant research challenge and needs to consider factors such as economics, reproducibility of results, delivery agent-drug complex stability and improved efficacy. 
     2. Description of Related Art 
     In the scientific literature there exist a number of methods to deliver pharmaceutical agents by binding or encasing the drug with another structure. One method being developed to improve the delivery of drugs is aptamers. Aptamers are nucleic acid sequences which can bind specific targets. For example, the formulation of aptamer-coated particles containing paclitaxel-polylactide nanoconjugates were developed to target cancer cells. 
     Nanoparticles composed of various organic and inorganic compositions have been developed and are in various stages of development for the delivery of medicinal agents. The role of nanoparticles is expected to both improve and provide new delivery agents for the pharmaceutical industry for decades. Nanoparticles enter the cell through a process known as endocyctosis; a process in which the material is engulfed by the cell wall. 
     Taxol (paclitaxel) is a natural product extracted from the bark of a yew tree. It is one of the most utilized drugs for the treatment of different cancers including breast, ovarian, central nervous system cancer (CNS), neck maladies, etc. Taxol, a mitotic inhibitor, has been produced by its ground-breaking total synthesis and semi-synthesis. While there is an extensive volume of studies relating to taxol and other taxanes, little work exists on its binding to cations, particularly any of the transition metals. The iron-taxol complex was synthesized and tested against the National Cancer Institute&#39;s sixty cell line cancer panel. The iron-taxol complex had activity significantly lower than pure taxol. Rather than enhance the taxol efficacy, iron(III) binding to the amine containing pharmaceutical agent lowered its pharmaceutical activity. This work demonstrated that any cation binding to an amine containing pharmaceutical agent will not enhance the drugs activity. There is selectivity to the copper ion. 
     One of the earliest nanoparticle delivery systems tested were liposomes. These systems are essentially biological micelles, having structure forms of molecular chains that have an external component which is polar and an internal component that is nonpolar. Liposomes can generally be divided into two groups (1) multilayers where there are several molecular layers composing the internal and external components (2) Unilamellar are one layer structures. The structure of the single and multilayer composites can be altered to increase or decrease water solubility and subsequently their drug delivery efficiency. 
     Methods have been developed that focus on specifically delivering amine containing pharmaceutical agents that are currently on the market. A U.S. patent exists that outlines a method of using bases to increase the permeation of amine drugs across the skin (U.S. Pat. No. 6,719,997). The patent covers a wide range of amine drugs which includes a variety of compounds used to treat Alzheimer&#39;s disease, enlarged prostates, and acid reflux disease. 
     The human protein albumin has been demonstrated to be an effective delivery platform for taxol. Albumin has higher water solubility than taxol. The use of the albumin is often referred to as a nanoparticulate formulation despite being a naturally occurring biomolecule. It has been approved, in 2005, for applications in patients with metastatic breast cancer who have been through other treatments but failed. The albumin-taxol combination is one example of the use of nanometer sized delivery agents. 
     In general nanoparticles are being investigated as delivery agents for many pharmaceuticals for a number of reasons including; (1) Nanoparticle size and surface parameters can be altered to achieve different transport properties (2) Nanoparticles can be designed to allow a controlled release of the drug while being transported through the patient or released (3) Nanoparticles can be administrated using different methods, including nasal, oral, intra-ocular, parenteral, and subcutaneous (4) Nanoparticles can be functionalized by molecular ligands altering which pharmaceutical site they target (5) Nanoparticles can be magnetic in nature and be guided to a specific location using magnetic fields (6) Nanoparticle composition can vary from iron oxide nanoparticles to naturally occurring proteins. While they can be as small as two or three nanometers in diameter, nanoparticles do have a high surface area and can aggregate and precipitate. 
     Copper sulfate (CuSO 4 ) has a lethality dose (LD 50 ) of approximately 30 milligrams of the copper salt per kilogram of rat (30 mg/kg). In adult humans, it requires gram quantities of copper sulfate to be lethal. In drinking water, the suggested safe level of copper is approximately 2 parts per million or 2.0 milligram/liter. In all applications proposed here, substantially lower levels of copper are proposed and the levels that would result from a typical copper (II) cation-pharmaceutical agent complex would be on par with the copper intake in a healthy diet. 
     For example, binding the copper (II) ion to taxol in a 1:1 complex, means that for every one mole of taxol (853 g/mol) there would be 1 mole of copper ion (63.5 g/mol) or the mass of copper would be less than ten percent the mass of taxol. Currently, taxol is sold in different formulations but some common ones are 30 milligrams (in 5 mL); 100 milligrams (in 16.7 mL), and 300 milligrams (in 50 mL) in multidose vials. In this commercially available formulation, each milliliter of the sterile solution contains 6 milligrams of taxol (paclitaxel), 527 milligrams of Cremophor® EL (polyoxyethylated castor oil) and 50% (volume/volume) of a dehydrated alcohol. In these formulations, if copper was included, the dose would contain less than one milligram of the copper cation. 
     The copper (II) cation has been shown to promote angiogenic responses. These observations have led to the development of anti-copper-based, anti-angiogenic strategies for the treatment of different types of cancer. Many researchers believe that Copper is a switch that turns on the angiogenesis process in tumor cells. It has been observed that patients with many types of progressive tumors typically have very high copper levels in the tumor region. Binding an amine containing drug to a copper ion will serve to block that amine site from being sidetracked by existing copper ions, in their different physiological environments. This allows the free Copper-amine complex (i.e. Cu-taxol) to by-pass the existing copper complexes, existing in the cancerous regions, and attacks its medicinal target. 
     Quinine is a natural product that has been used, directly and indirectly, by cultures around the world for hundreds of years. Its first recorded use was by Indians in Peru over four hundred years ago. The native Peruvian population used the bark of the cinchona tree to treat shivering and aches associated with malaria and other maladies. Spanish explorers observed this use in their 17 th  century explorations and brought the tree back to Europe for cultivation. Since that time, extracts of the tree have been used to treat the symptoms of malaria around the world. European explorers in Africa, Central and South America, parts of the South Pacific, etc. were routinely stopped in their various quests by the onset of malaria. During significant events in the history of the United States, such as the Civil War battles in the Deep South, digging the Panama Canal and fighting in the Pacific theater during World War II, quinines presence, or lack thereof, dramatically impacted the outcome of events and the fate of the participants. For centuries the cinchona tree remained the only viable source of quinine. 
     In 1944 Robert Woodward and William von Eggers Doering published the total synthesis of quinine. This synthesis was significant for two reasons; the production of quinine could be attained without the cinchona tree, whose growth was limited to specific locations. During World War II there were supply problems with quinine for U.S. troops in the South Pacific. This synthesis raised hope that the supply issues could be solved. Second, the seventeen step procedure was billed as one of the first, large scale total synthesis of any natural product. It turns out that the Woodard-Doering synthesis actually did not produce quinine but a precursor that could be converted to quinine by the Rabe-Kindler synthesis, published in 1918. The Woodard-Doering and Rabe-Kindler synthesis were refuted by Gilbert Stork but, this controversy was later resolved in favor of the original authors. 
     Quinine (Qualaquin) has been approved by the Food and Drug Administration in treating malaria. It has been used for treating leg cramps, which is not approved by the FDA. Ingesting excessive quinine results in severe side effects including chills and fever, irregular heartbeats, loss of hearing and/or vision, yellowed skin, stomach pain and diarrhea and significant skin rashes. Excessive intake of quinine can result in death. For malaria patients, adults can be prescribed up to 500 mg per dose, taken up to three times per day. Quinine has a poor solubility in water (approximately 0.5 g/liter) but is readily soluble in ethanol and chloroform. 
     Quinine, a simple alkaloid, has found little use in treating cancer but it has been evaluated as a chemosensitizer in conjunction with taxol. Using quinine with taxol can increase taxol&#39;s anti-cancer activity. Understanding a medicinal agent equilibrium reaction with cations in the body can help explain their activities and side effects. Taxol, a cancer drug with a single amine, can bind copper ions (I or II), as can quinine. If quinine, with two amines, is administered with taxol but at higher concentrations, taxol&#39;s efficiency increases. 
       Taxol(aq)+Cu 2+ (aq)===Cu(taxol) 1 (aq)K 1   (1)
 
       Quinine+Cu 2+ (aq)===Cu(quinine) 1 (aq)K 2   (2)
 
     Taxol&#39;s increase in medical efficiency in that study can be explained as follows. Quinine binds the available or exposed naturally occurring copper in the body allowing the cancer drug to reach its medicinal target more efficiently. Lech and Sladick found that copper levels in different organs in the body (130 bodies sampled) ranged from approximately one to three parts per million or a fifty kilogram adult would have up to 0.15 grams of copper in their body. While there will be low levels of free copper in the body, most of it is bound in macromolecules involved in some essential biological function. Taxol binding copper that is already involved in an essential physiological process can not only sidetrack the taxol from its intended medicinal target but disrupt the original physiological process inducing side effects. Quinine, which has lower toxicity than taxol against all types of cancer, may bind or tie up these copper ions, allowing the taxol to reach its pharmaceutical destination with a higher degree of efficiency. Despite the water solubility limitations of common amines such as taxol and quinine, and the extensive work conducted using large structures such as nanoparticles and proteins, nothing has been done to improve the solubility using cations. 
     Scientists have measured the acid-base equilibrium constants (i.e. pK a &#39;s) of quinine as well as three other drugs that had acidic functional groups. These values were measured at different ionic strengths (0.01 to 1) and temperatures (25 and 37° C.). For quinine&#39;s two amines, pK a1  was measured to be approximately 4.2 and pK a2  was 8.5. pK a &#39;s and electron affinities of ligands have been correlated with the stability constants of metal ligand complexes. Copper-ethylene (en) stability constants have been compared to other transition metals and are typically larger and more stable. This correlation among transition metals is known as the Irving-Williams series and indicates that copper forms the strongest complexes with amines. The stability trend that follows is: 
       Mn(II)&lt;Fe(II)&lt;Co(II)&lt;Ni(II)&lt;Copper(II)&gt;Zn(II)  (3)
 
     Scientists have identified a new copper(II)-quinine complex [Cu(C 20 H 23 O 2 N 2 )(OH 2 ) 2 ]ClO 4 . The solid state complex was analyzed using infrared spectroscopy, electron paramagnetic resonance (EPR) and thermal analysis. The research results suggested that both amine sites were bound by Copper(II) ions but did not investigate the solution phase structure. The published work also showed the Copper(II)-quinine complex (CuQ; Q=quinine) was octahedral, not unlike most Copper(II) complexes. Given the work did not use a definitive technique to identify the structure, such as nuclear magnetic resonance, its exact structure can only be suggested. 
     Past quinine work in this lab involved a field project along the Suwannee River (Florida, USA) in which quinine, minus its methoxy group, was found in a number of sediment samples. This find was correlated with U.S. Civil War history in which locals used the extracts from the bark of a dogwood tree to relieve the symptoms of malaria when quinine was not available due to a naval blockade. While quinine is a well-known natural product and copper(II) a likely candidate to be investigated as a binding partner, no definitive study in the literature exists to understand the Cu 1 Q 1 , Cu 1 Q 2  or a quinine dimer complex structure in the solution phase, which is important for medicinal applications. 
     The World Health Organization lists over three hundred medicines it considers essential for the various maladies that impact the entire human population. Approximately one hundred and forty of these are nitrogen containing drugs. The copper(II) ion can be used as a delivery platform for these drugs with little added expense. Table one provides the list of the drugs, the disease they are used to treat and additional information. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 A list of nitrogen containing drug the World Health Organization 
               
               
                 considers essential for the basic human health needs. 
               
            
           
           
               
               
               
               
            
               
                 Name 
                 Treatment 
                 Molecular Weight 
                 Empirical Formula 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Neomycin Sulfate + 
                 Used in combination 
                 614.644 
                 g/mol 
                 C 23 H 46 N 6 O × 
               
               
                 Bacitracin 
                 together as a topical 
                   
                   
                 2½ H 2 SO 4   
               
               
                   
                 ointment to fight infection 
               
               
                   
                 and speed up healing of 
               
               
                   
                 wounds. Together make up 
               
               
                   
                 Neosporin. 
               
               
                 Isoniazid + 
                 Isoniazid by itself was one 
                 137.139 
                 g/mol 
                 Isoniazid: C 6 H 7 N 3 O 
               
               
                 Ethambutol 
                 of the first anti-depressants 
                   
                   
                 Ethambutol: C 5 H 12 NO 
               
               
                   
                 discovered, but when used in 
               
               
                   
                 combination with 
               
               
                   
                 ethambutol it is used as a 
               
               
                   
                 first line anti-tuberculosis 
               
               
                   
                 medication and prevention. 
               
               
                 Abacavir 
                 A nucleoside reverse 
                 286.332 
                 g/mol 
                 C 14 H 18 N 6 O 
               
               
                   
                 transcriptase inhibitor that is 
               
               
                   
                 used to treat HIV/Aids. Its 
               
               
                   
                 trade name is Ziagen and its 
               
               
                   
                 main side effect is 
               
               
                   
                 hypersensitivity. 
               
               
                 Sulfadoxine + 
                 Used in combination 
                 310.33 
                 g/mol 
                 Sulfadoxine: C 12 H 14 N 4 O 4 S 
               
               
                 Pyrimethamine 
                 together to treat and prevent 
                   
                   
                 Pyrimethamine: C 12 H 13 CIN 4   
               
               
                   
                 malaria. Used in treatment 
               
               
                   
                 of  Toxoplasma gondii   
               
               
                   
                 infections in 
               
               
                   
                 immunocompromised 
               
               
                   
                 patients such as HIV+ 
               
               
                   
                 individuals. 
               
               
                 Primaquine 
                 Used in the treatment of 
                 259.347 
                 g/mol 
                 C 15 H 21 N 3 O 
               
               
                   
                 malaria and Pneumocystis 
               
               
                   
                 pneumonia. It causes 
               
               
                   
                 methemoglobinemia in all 
               
               
                   
                 patients who take it. 
               
               
                 Sulfadiazine 
                 Used to treat urinary tract 
                 250.278 
                 g/mol 
                 C 10 H 10 N 4 O 2 S 
               
               
                   
                 infections by stopping the 
               
               
                   
                 production of folic acid in 
               
               
                   
                 bacterial cell walls. Side 
               
               
                   
                 effects include loss of 
               
               
                   
                 appetite, nausea, upset 
               
               
                   
                 stomach, and dizziness. 
               
               
                 Levodopa + 
                 Used in combination to treat 
                 197.19 
                 g/mol + 
                 Leodopa: C 9 H 4 NO 4   
               
               
                 Carbidopa 
                 Parkinson&#39;s disease. The 
                 226.229 
                 g/mol 
                 Carbidopa: C 5 H 7 NO 2   
               
               
                   
                 combination of the two 
               
               
                   
                 reduces the side effects than 
               
               
                   
                 if one is used alone. 
               
               
                 Rifampicin + 
                 Used in combination as first 
                 822.94 
                 g/mol + 
                 Pyrizinamide: C 5 H 5 N 3 O 
               
               
                 Pyrazinamide + 
                 line defense against 
                 123.113 
                 g/mol + 
               
               
                 Isoniazide + 
                 tuberculosis. First 
                 137.139 
                 g/mol + 
               
               
                 Ethambutol 
                 phase/line dosaging for 
                 204.31 
                 g/mol 
               
               
                   
                 tuberculosis caused from 
               
               
                   
                   Mycobacterium tuberculosis . 
               
               
                 Trimethoprim 
                 Treatment for prophylaxis 
                 290.32 
                 g/mol 
                 C 14 H 18 N 4 O 3   
               
               
                   
                 and urinary tract infections. 
               
               
                   
                 Also known as a 
               
               
                   
                 dihydrofolate reductase 
               
               
                   
                 inhibitor. 
               
               
                 Tenofovir 
                 Used in treatment of HIV 
                 287.213 
                 g/mol 
                 C 9 H 14 N 5 O 4 P 
               
               
                   
                 and Hepatits B. Reduces 
               
               
                   
                 infection rate of both 
               
               
                   
                 viruses. 
               
               
                 Sulfasalazine 
                 Used for rheumatoid 
                 398.394 
                 g/mol 
                 C 18 H 14 N 4 O 5 S 
               
               
                   
                 arthritis, ensethitis, and as an 
               
               
                   
                 anti-inflammatory agent in 
               
               
                   
                 inflammatory bowel disease. 
               
               
                 Acyclovir 
                 Used for treatment of herpes 
                 225.21 
                 g/mol 
                 C 8 H 11 N 5 O 3   
               
               
                   
                 simplex virus, chicken pox, 
               
               
                   
                 and shingles. 
               
               
                 Propythiouracil 
                 Treats hyperthyroidism, but 
                 170.233 
                 g/mol 
                 C 7 H 10 N 2 O 5   
               
               
                   
                 has a serious risk of liver 
               
               
                   
                 problems and is no longer 
               
               
                   
                 recommended as a primary 
               
               
                   
                 source of medicine. 
               
               
                 Chloroquine 
                 Used in the treatment of 
                 319.872 
                 g/mol 
                 C 18 H 26 ClN 3   
               
               
                   
                 malaria. Mildly suppresses 
               
               
                   
                 the immune system so also 
               
               
                   
                 used in some autoimmune 
               
               
                   
                 diseases. 
               
               
                 P-Aminosalicylic 
                 The second antibiotic found 
                 153.135 
                 g/mol 
                 C 7 H 7 NO 3   
               
               
                 Acid 
                 to be effective in treating 
               
               
                   
                 tuberculosis. Also treats 
               
               
                   
                 inflammatory bowel disease. 
               
               
                 Emtricitabine 
                 Used in treatment of HIV in 
                 247.248 
                 g/mol 
                 C 8 H 10 FN 3 O 3 S 
               
               
                   
                 adults and children. Also 
               
               
                   
                 used in treatment of hepatitis 
               
               
                   
                 B. 
               
               
                 Kanamycin 
                 Used to treat many various 
                 484.499 
                 g/mol 
                 C 18 H 36 N 4 O 11   
               
               
                   
                 types of infections and can 
               
               
                   
                 be administered orally, 
               
               
                   
                 intravenously, or 
               
               
                   
                 intramuscularlry. 
               
               
                 Fluconazole 
                 Used in the treatment and 
                 306.271 
                 g/mol 
                 C 13 H 12 F 2 N 6 O 
               
               
                   
                 prevention of superficial and 
               
               
                   
                 systematic fungal infections. 
               
               
                 Ofloxacin 
                 A racemic mixture molecule 
                 361.368 
                 g/mol 
                 C 18 H 20 FN 3 O 4   
               
               
                   
                 which is used as a 
               
               
                   
                 chemotherapeutic antibiotic 
               
               
                   
                 of the fluoroquinine drug 
               
               
                   
                 class. 
               
               
                 Streptomycin 
                 A bactericidal antibiotic 
                 581.574 
                 g/mol 
                 C 21 H 39 N 7 O 12   
               
               
                   
                 used as a remedy for 
               
               
                   
                 tuberculosis which is given 
               
               
                   
                 intramuscularly. 
               
               
                 Codeine 
                 Used to treat moderate pain 
                 299.364 
                 g/mol 
                 C 18 H 21 NO 3   
               
               
                   
                 and cough. Also used to 
               
               
                   
                 treat diarrhea. 
               
               
                 Urea 
                 Used dermatologically to 
                 4.66 
                 debye 
                 CH 4 N 2 O 
               
               
                   
                 promote skin rehydration. 
               
               
                   
                 Treats psoriasis, xerosis, 
               
               
                   
                 eczema, keratosis and many 
               
               
                   
                 other “dry skin” diseases. 
               
               
                   
                 Urea injections are used for 
               
               
                   
                 abortions. 
               
               
                 Amodiaquine 
                 Used as an anti-malarial and 
                 355.861 
                 g/mol 
                 C 20 H 22 ClN 3 O 
               
               
                   
                 anti-inflammatory agent. 
               
               
                   
                 Not marketed in USA, but 
               
               
                   
                 widely used in Africa. 
               
               
                 Fluorouracil 
                 Used in the treatment of 
                 130.077 
                 g/mol 
                 C 4 H 3 FN 2 O 2   
               
               
                   
                 cancer by inhibiting the 
               
               
                   
                 growth of skin cells. It will 
               
               
                   
                 harm an unborn child if used 
               
               
                   
                 as a topical agent. 
               
               
                 Doxycycline 
                 Treats common 
                 462.46 
                 g/mol 
                 C 22 H 24 N 2 O 8   
               
               
                   
                 inflammation as well as 
               
               
                   
                 sinusitis, prostatits, syphilis, 
               
               
                   
                 Chlamydia, and PID. Used 
               
               
                   
                 experimentally as a matrix 
               
               
                   
                 metalloprotease inhibitor. 
               
               
                 Mefloquine 
                 Used in the treatment and 
                 378.312 
                 g/mol 
                 C 17 H 16 F 6 N 2 O 
               
               
                   
                 prevention of mild malaria 
               
               
                   
                 infections. Can cause 
               
               
                   
                 abnormal heart rhythms. 
               
               
                 Miconazole 
                 Topical treatment for fungal 
                 416.127 
                 g/mol 
                 C 18 H 14 Cl 4 N 2 O 
               
               
                   
                 infections; ringworm, jock- 
               
               
                   
                 itch, and athlete&#39;s foot. Kills 
               
               
                   
                 fungal cells by preventing 
               
               
                   
                 the synthesis of ergosterol. 
               
               
                   
                 Applied internally for yeast 
               
               
                   
                 infections. 
               
               
                 Biperiden 
                 Used in the treatment of 
                 311.461 
                 g/mol 
                 C 21 H 29 NO 
               
               
                   
                 Parkinson&#39;s disease. 
               
               
                   
                 Relieves muscle rigidity and 
               
               
                   
                 abnormal sweating. 
               
               
                 Didanosine 
                 A reverse transcriptase 
                 236.227 
                 g/mol 
                 C 10 H 12 N 4 O 3   
               
               
                   
                 inhibitor that is used as an 
               
               
                   
                 effective treatment against 
               
               
                   
                 HIV. 
               
               
                 Levothyroxine 
                 Used to treat 
                 776.87 
                 g/mol 
                 C 15 H 11 I 4 NO 4   
               
               
                   
                 hypothyroidism by 
               
               
                   
                 controlling TSH. It is a 
               
               
                   
                 hormone replacement. 
               
               
                 Benzylpenicillin 
                 Used in the treatment of 
                 334.4 
                 g/mol 
                 C 16 H 18 N 2 O 4 S 
               
               
                   
                 celluitis, bacterial 
               
               
                   
                 endocarditis, diarrhea, 
               
               
                   
                 gangrene, gonorrhea, 
               
               
                   
                 meningitis, pneumonia, 
               
               
                   
                 syphilis, septicemia, and 
               
               
                   
                 septic arthritis. 
               
               
                 Glibenclamide 
                 Used in the treatment of type 
                 494.004 
                 g/mol 
                 C 23 H 28 ClN 3 O 5 S 
               
               
                   
                 II diabetes by stimulating 
               
               
                   
                 insulin release by inhibiting 
               
               
                   
                 ATP-sensitive potassium 
               
               
                   
                 cells in pancreatic beta cells. 
               
               
                 Stavudine 
                 Inhibits HIV reverse 
                 224.213 
                 g/mol 
                 C 10 H 12 N 2 O 4   
               
               
                   
                 transcriptase by competing 
               
               
                   
                 with thymidine triphosphate. 
               
               
                 Lamivudine 
                 Used to treat chronic 
                 229.26 
                 g/mol 
                 C 8 H 11 N 3 O 3 S 
               
               
                   
                 hepatitis B and HIV by 
               
               
                   
                 inhibiting reverse 
               
               
                   
                 transcriptase. 
               
               
                 Clotrimazole 
                 Used to treat vaginal yeast 
                 334.837 
                 g/mol 
                 C 22 H 17 ClN 2   
               
               
                   
                 infections, oral thrush, and 
               
               
                   
                 ringworm. 
               
               
                 Quinine 
                 First effective treatment for 
                 324.417 
                 g/mol 
                 C 20 H 24 N 2 O 2   
               
               
                   
                 malaria. Very sensitive to 
               
               
                   
                 UV light. Naturally 
               
               
                   
                 occurring from the cinchoa 
               
               
                   
                 tree. 
               
               
                 Metformin 
                 Oral treatment for type 2 
                 129.164 
                 g/mol 
                 C 4 H 11 N 5   
               
               
                   
                 diabetes by suppressing 
               
               
                   
                 glucose production of the 
               
               
                   
                 liver and increasing insulin 
               
               
                   
                 sensitivity. 
               
               
                 Oxamniquine 
                 Used to treat worms in the 
                 279.3 
                 g/mol 
                 C 14 H 21 N 3 O 3   
               
               
                   
                 body. Causes worms to shift 
               
               
                   
                 from the mesenteric veins to 
               
               
                   
                 the liver. 
               
               
                 Benzathine 
                 Used in the treatment of 
                 240.343 
                 g/mol + 
                 Benzathine: C 16 H 20 N 2   
               
               
                 benzypenicillin 
                 early or latent syphilis and 
                 390.4 
                 g/mol 
                 Benzylpenicillin: C 16 H 18 N 2 O 4 S 
               
               
                   
                 prevention of rheumatic 
               
               
                   
                 fever. 
               
               
                 Nitrofurantoin 
                 Damages bacterial DNA and 
                 238.16 
                 g/mol 
                 C 8 H 6 N 4 O 5   
               
               
                   
                 helps in the treatment of 
               
               
                   
                 urinary tract infections. 
               
               
                 Efavirenz 
                 Used in the treatment of 
                 315.675 
                 g/mol 
                 C 14 H 9 ClF 3 NO 2   
               
               
                   
                 HIV. Always used in 
               
               
                   
                 combination with other 
               
               
                   
                 drugs, never used alone. 
               
               
                 Pentamidine 
                 Used in the prevention of 
                 340.42 
                 g/mol 
                 C 19 H 24 N 4 O 2   
               
               
                   
                 Pneumocytosis pneumonia, 
               
               
                   
                 used as a prophylactic 
               
               
                   
                 against PCP in chemo 
               
               
                   
                 patients, and treats 
               
               
                   
                 leishmaniasis and yeast 
               
               
                   
                 infections. 
               
               
                 Triclabendazole 
                 Treatment for liver flukes. 
                 359.658 
                 g/mol 
                 C 14 H 9 Cl 3 N 2 OS 
               
               
                   
                 Prevents the polymerization 
               
               
                   
                 of microtubules. 
               
               
                 Cloxacillin 
                 Same family of medicine as 
                 435.88 
                 g/mol 
                 C 19 H 18 ClN 3 O 5 S 
               
               
                   
                 penicillin and is used against 
               
               
                   
                 staphylococci that produce 
               
               
                   
                 B-lactamases. 
               
               
                 Chloramphenicol 
                 Used to treat typhoid and is 
                 323.132 
                 g/mol 
                 C 11 H 12 Cl 2 N 2 O 5   
               
               
                   
                 also effective against Gram- 
               
               
                   
                 positive and Gram-negative 
               
               
                   
                 bacteria. Inhibits bacterial 
               
               
                   
                 protein synthesis. 
               
               
                 Amikacin 
                 An antibiotic that fights 
                 585.603 
                 g/mol 
                 C 22 H 43 N 5 O 13   
               
               
                   
                 against bacteria. Used to 
               
               
                   
                 treat severe, hospital- 
               
               
                   
                 acquired infections. Must be 
               
               
                   
                 administered intravenously 
               
               
                   
                 or intra muscularly. 
               
               
                 Ciprofloxacin 
                 Treats infection such as 
                 331.346 
                 g/mol 
                 C 17 H 18 FN 3 O 3   
               
               
                   
                 endocarditis, gastroenteritis, 
               
               
                   
                 respiratory tract infections, 
               
               
                   
                 urinary tract infections, 
               
               
                   
                 cellulitis, anthrax and more. 
               
               
                   
                 300 trade names. 
               
               
                 Ceftazidime 
                 Used to treat bacterial 
                 546.58 
                 g/mol 
                 C 22 H 22 N 6 O 7 S 2   
               
               
                   
                 infections especially those of 
               
               
                   
                   Pseudomonas aeruginosa . 
               
               
                 Metronidazole 
                 Treats bacterial skin 
                 171.15 
                 g/mol 
                 C 6 H 9 N 3 O 3   
               
               
                   
                 infections of the stomach, 
               
               
                   
                 vagina, skin, joints, and 
               
               
                   
                 respiratory tract. Treats 
               
               
                   
                 dermatological conditions 
               
               
                   
                 like rosacea. 
               
               
                 Spectinomycin 
                 Treats gonorrhea in patients 
                 332.35 
                 g/mol 
                 C 14 H 24 N 2 O 7   
               
               
                   
                 allergic to penicillin. 
               
               
                   
                 Interrupts bacterial protein 
               
               
                   
                 synthesis. 
               
               
                 Dapsone 
                 Used for the treatment of 
                 248.302 
                 g/mol 
                 C 12 H 12 N 2 O 2 S 
               
               
                   
                 leprosy and Pneumocytosis 
               
               
                   
                 pneumonia. Used in multi- 
               
               
                   
                 drug therapy. 
               
               
                 Praziquantel 
                 Used to treat flatworm 
                 312.411 
                 g/mol 
                 C 19 H 24 N 2 O 2   
               
               
                   
                 infections including 
               
               
                   
                 nematode, tapeworm, and 
               
               
                   
                 fluke infections. 
               
               
                 Ethionamide 
                 Used as an antibiotic to treat 
                 166.244 
                 g/mol 
                 C 8 H 10 N 2 S 
               
               
                   
                 tuberculosis. 
               
               
                 Cefixime 
                 Used to treat infections 
                 435.452 
                 g/mol 
                 C 16 H 15 N 5 O 7 S 2   
               
               
                   
                 caused by bacteria such as 
               
               
                   
                 bronchitis, gonorrhea, and 
               
               
                   
                 pneumonia, as well as ear, 
               
               
                   
                 lung throat, and urinary tract 
               
               
                   
                 infections. 
               
               
                 Ampicillin 
                 Used to treat many bacterial 
                 349.41 
                 g/mol 
                 C 16 H 19 N 3 O 4 S 
               
               
                   
                 infections. 
               
               
                 Clindamycin 
                 Used as a topical treatment 
                 424.98 
                 g/mol 
                 C 18 H 33 ClN 2 O 5 S 
               
               
                   
                 for acne and for infections 
               
               
                   
                 caused by anaerobic 
               
               
                   
                 bacteria. 
               
               
                 Cefazolin 
                 Used in treatment of 
                 454.51 
                 g/mol 
                 C 14 H 14 N 8 O 4 S 3   
               
               
                   
                 bacterial infections of skin, 
               
               
                   
                 lung, bone, joint, stomach, 
               
               
                   
                 blood, heart valve, and 
               
               
                   
                 urinary tract. 
               
               
                 Zidovudine 
                 Used in treatment of mother- 
                 267.242 
                 g/mol 
                 C 10 H 13 N 5 O 4   
               
               
                   
                 child transmission of HIV 
               
               
                   
                 during pregnancy, labor and 
               
               
                   
                 delivery. 
               
               
                 Cycloserine 
                 Used to treat tuberculosis. 
                 102.092 
                 g/mol 
                 C 3 H 6 N 2 O 2   
               
               
                 Nevirapine 
                 Used in treatment of HIV-1 
                 266.888 
                 g/mol 
                 C 15 H 14 N 4 O 
               
               
                   
                 and AIDS. 
               
               
                 Diethylcarbamazine 
                 Used in the treatment of 
                 199.293 
                 g/mol 
                 C 10 H 21 N 3 O 
               
               
                   
                 parasites. 
               
               
                 Gentamicin 
                 Synthesized by a gram- 
                 477.596 
                 g/mol 
                 C 21 H 43 N 5 O 7   
               
               
                   
                 positive bacteria and used to 
               
               
                   
                 treat many gram-negative 
               
               
                   
                 bacterial infections. 
               
               
                 Flucytosine 
                 Used to treat fungal 
                 129.093 
                 g/mol 
                 C 4 H 4 FN 3 O 
               
               
                   
                 infections. 
               
               
                 Co-amoxiclav 
                 An antibiotic used to treat 
                 365.4 
                 g/mol + 
                 C 16 H 19 N 3 O 5 S + 
               
               
                 (combination of 
                 against amoxicillin-resistant 
                 199.16 
                 g/mol 
                 C 8 H 9 NO 5   
               
               
                 amoxicillin and 
                 bacteria. Effective against 
               
               
                 clavulanic acid) 
                   Klebsiella  infections but not 
               
               
                   
                   Pseudomonas . 
               
               
                 Silver sulfadiazine 
                 Used as a topical to treat 
                 357.14 
                 g/mol 
                 C 10 H 9 AgN 4 O 2 S 
               
               
                   
                 burns and prevents the 
               
               
                   
                 growth of bacteria and yeast. 
               
               
                 Ribavirin 
                 Used in the treatment for 
                 244.206 
                 g/mol 
                 C 8 H 12 N 4 O 5   
               
               
                   
                 severed respiratory syncytial 
               
               
                   
                 virus and hepatitis C. 
               
               
                 Phenytoin 
                 Suppresses abnormal brain 
                 252.268 
                 g/mol 
                 C 15 H 12 N 2 O 2   
               
               
                   
                 activity during a seizure. 
               
               
                 Capreomycin 
                 Used in combination with 
                 668.706 
                 g/mol 
                 C 25 H 44 N 14 O 8   
               
               
                   
                 other drugs for the treatment 
               
               
                   
                 of tuberculosis. 
               
               
                 Procaine Penicillin 
                 Combination of an 
                 236.31 
                 g/mol + 
                 C 13 H 20 N 2 O 2  + 
               
               
                   
                 anesthetic and antibiotic. 
                 334.4 
                 g/mol 
                 C 16 H 18 N 2 O 4 S 
               
               
                   
                 Treats syphilis, respiratory 
               
               
                   
                 tract infections, strep throat, 
               
               
                   
                 cellulitis, and erysipelas. 
               
               
                 Co-Trimaoxazole 
                 Treats upper and lower 
                 331.783 
                 g/mol 
                 C 14 H 19 N 4 O 3   
               
               
                   
                 respiratory tract infections, 
               
               
                   
                 renal urinary tract infections, 
               
               
                   
                 gastrointestinal infections, 
               
               
                   
                 and skin infections. 
               
               
                 Ceftriaxone 
                 Treats community-acquired 
                 554.58 
                 g/mol 
                 C 18 H 18 N 8 O 7 S 3   
               
               
                   
                 or mild to moderate health 
               
               
                   
                 care-associated pneumonia. 
               
               
                   
                 Also used to treat bacterial 
               
               
                   
                 meningitis, lyme disease, 
               
               
                   
                 typhoid fever, gonorrhea, 
               
               
                   
                 and chlamydia 
               
               
                 Pyrantel 
                 Antiworm medication used 
                 206.31 
                 g/mol 
                 C 11 H 14 N 2 S 
               
               
                   
                 to treat roundworm, 
               
               
                   
                 hookworm, pinworm, and 
               
               
                   
                 other worm infections. 
               
               
                 Mebendazole 
                 Used to treat infestations of 
                 295.293 
                 g/mol 
                 C 16 H 13 N 3 O 3   
               
               
                   
                 worms including, pinworms, 
               
               
                   
                 roundworms, tapeworms, 
               
               
                   
                 hookworms, and whipworms. 
               
               
                 Levamisole 
                 Used in the treatment of 
                 204.292 
                 g/mol 
                 C 11 H 12 N 2 S 
               
               
                   
                 parasitic worm infections. Is 
               
               
                   
                 used as a “dewormer” for 
               
               
                   
                 livestock. 
               
               
                 Niclosamide 
                 Used to specifically treat 
                 327.119 
                 g/mol 
                 C 13 H 8 Cl 2 N 2 O 4   
               
               
                   
                 tapeworms and cestodes in 
               
               
                   
                 humans. 
               
               
                 Promethazine 
                 Treats allergic reactions 
                 284.42 
                 g/mol 
                 C 17 H 20 N 2 S 
               
               
                   
                 such as allergic rhinitis, 
               
               
                   
                 relaxes and sedates patients 
               
               
                   
                 before and after surgery or 
               
               
                   
                 during labor. 
               
               
                 Metoclopramide 
                 Used to relieve heartburn 
                 299.8 
                 g/mol 
                 C 14 H 22 ClN 3 O 2   
               
               
                   
                 and speed the healing of 
               
               
                   
                 ulcers and sores in the 
               
               
                   
                 esophagus. 
               
               
                 Chlorpromazine 
                 Used in the treatment of 
                 318.86 
                 g/mol 
                 C 17 H 19 ClN 2 S 
               
               
                   
                 schizophrenia and other 
               
               
                   
                 psychotic disorders, as well 
               
               
                   
                 as mania in people who have 
               
               
                   
                 bipolar disorder. 
               
               
                 Fluphenazine 
                 Used to treat symptoms of 
                 437.523 
                 g/mol 
                 C 22 H 28 F 3 N 3 OS 
               
               
                   
                 schizophrenia and psychotic 
               
               
                   
                 symptoms such as 
               
               
                   
                 hallucinations, delusions, 
               
               
                   
                 and hostility. Also treats 
               
               
                   
                 acute manic phases and 
               
               
                   
                 hostility. 
               
               
                 Fluoxetine 
                 Treats major depression, 
                 309.33 
                 g/mol 
                 C 17 H 18 F 3 NO 
               
               
                   
                 OCD, bulimia, and panic 
               
               
                   
                 disorder. 
               
               
                 Methadone 
                 Used to manage chronic pain 
                 309.445 
                 g/mol 
                 C 21 H 27 NO 
               
               
                 Meglumine 
                 A contrast dye injected into 
                 141.78 
                 g/mol 
                 C 6 H 15 NO 5   
               
               
                 iotroxate 
                 body before some x-ray 
               
               
                   
                 procedures. 
               
               
                 Phenobarbital 
                 Commonly used to treat 
                 232.235 
                 g/mol 
                 C 12 H 12 N 2 O 3   
               
               
                   
                 neonatal seizures. It acts as 
               
               
                   
                 a central nervous system 
               
               
                   
                 depressant. Also used to 
               
               
                   
                 treat stress, anxiety, and 
               
               
                   
                 prevent withdrawal 
               
               
                   
                 symptoms of people who are 
               
               
                   
                 dependent. 
               
               
                 Penicillamine 
                 Used as a form of 
                 149.212 
                 g/mol 
                 C 5 H 11 NO 2 S 
               
               
                   
                 immunosuppressant to treat 
               
               
                   
                 rheumatoid arthritis. Also 
               
               
                   
                 used to treat Wilson&#39;s 
               
               
                   
                 disease. 
               
               
                 Allopurinol 
                 Treats kidney stones and can 
                 136.112 
                 g/mol 
                 C 5 H 4 N 4 O 
               
               
                   
                 lower blood pressure in mild 
               
               
                   
                 hypertension. 
               
               
                 Ethosuxamide 
                 Used for treatment of 
                 141.168 
                 g/mol 
                 C 7 H 11 NO 2   
               
               
                   
                 absence seizures. 
               
               
                 Amiloride 
                 Treats congestive heart 
                 229.67 
                 g/mol 
                 C 6 H 8 ClN 7 O 
               
               
                   
                 failure, edema associated 
               
               
                   
                 with kidney and liver 
               
               
                   
                 diseases and hypertension. 
               
               
                   
                 Also promotes the loss of 
               
               
                   
                 sodium and water from 
               
               
                   
                 body. 
               
               
                 Furosemide 
                 Treats edema in people with 
                 340.745 
                 g/mol 
                 C 12 H 11 ClN 2 O 5 S 
               
               
                   
                 congestive heart, failure, 
               
               
                   
                 liver disease, or kidney 
               
               
                   
                 disorder. Also treats high 
               
               
                   
                 blood pressure. 
               
               
                 Haloperidol 
                 Treats symptoms of 
                 375.9 
                 g/mol 
                 C 21 H 23 ClFNO 2   
               
               
                   
                 schizophrenia, and treatment 
               
               
                   
                 of acute psychotic states and 
               
               
                   
                 delirium. Also used to 
               
               
                   
                 control motor tics in patients 
               
               
                   
                 who have Tourette&#39;s 
               
               
                   
                 disorder. 
               
               
                 Iohexol 
                 Used as a contrast agent 
                 821.138 
                 g/mol 
                 C 19 H 26 I 3 N 3 O 9   
               
               
                   
                 during coronary 
               
               
                   
                 angiography. 
               
               
                 Methotrexate 
                 Treats rheumatoid arthritis, 
                 454.44 
                 g/mol 
                 C 20 H 22 N 8 O 5   
               
               
                   
                 certain types of cancer, and 
               
               
                   
                 treats severe psoriasis by 
               
               
                   
                 slowing growth of skin cells. 
               
               
                 Ranitidine 
                 Treats ulcers and 
                 314.4 
                 g/mol 
                 C 13 H 22 N 4 O 3 S 
               
               
                   
                 gastroesophogeal reflux 
               
               
                   
                 disease, and helps to treat 
               
               
                   
                 Zollinger-Ellison syndrome. 
               
               
                 Bupropion 
                 Is a Norepinephrine- 
                 239.74 
                 g/mol 
                 C 13 H 18 ClNO 
               
               
                   
                 dopamine reuptake inhibitor. 
               
               
                   
                 Also an antidepressant and 
               
               
                   
                 smoking cessation aid. 
               
               
                 Pyridoxine 
                 Assists in the balancing of 
                 169.18 
                 g/mol 
                 C 8 H 11 NO 3   
               
               
                   
                 sodium and potassium as 
               
               
                   
                 well as promoting RBC 
               
               
                   
                 production. Vitamin B6. 
               
               
                 Ergometrine 
                 Facilitates the delivery of the 
                 325.41 
                 g/mol 
                 C 19 H 23 N 3 O 2   
               
               
                   
                 placenta after childbirth. 
               
               
                   
                 Causes smooth muscle tissue 
               
               
                   
                 in blood vessels to narrow, 
               
               
                   
                 reducing blood flow. 
               
               
                 Diazepam 
                 Is a psychoactive drug that is 
                 284.7 
                 g/mol 
                 C 16 H 13 ClN 2 O 
               
               
                   
                 used to treat anxiety, 
               
               
                   
                 insomnia, and symptoms of 
               
               
                   
                 acute alcohol withdrawal. 
               
               
                 Chlorhexidine 
                 Effective on gram-positive 
                 505.446 
                 g/mol 
                 C 22 H 30 Cl 2 N 10   
               
               
                   
                 and gram-negative bacteria, 
               
               
                   
                 and is often used in dental 
               
               
                   
                 mouthwash to reduce dental 
               
               
                   
                 plaque and oral bacteria. 
               
               
                 Epinephrine 
                 Increases heart rate, 
                 183.204 
                 g/mol 
                 C 9 H 13 NO 3   
               
               
                   
                 constricts blood vessels and 
               
               
                   
                 dilates air passages. Treats 
               
               
                   
                 cardiac arrest, anaphylaxis, 
               
               
                   
                 and superficial bleeding. 
               
               
                 Omeprazole 
                 Is a proton pump inhibitor 
                 345.4 
                 g/mol 
                 C 17 H 19 N 3 O 3 S 
               
               
                   
                 that can be given with 
               
               
                   
                 antibiotics to treat gastric 
               
               
                   
                 ulcers. Also used to treat 
               
               
                   
                 gastroesophageal reflux 
               
               
                   
                 disease. 
               
               
                 Sodium Calcium 
                 Treats led poisoning, and 
                 292.24 
                 g/mol 
                 C 10 H 16 N 2 O 8   
               
               
                 Edetate 
                 can take the hard metal out 
               
               
                   
                 of the blood. 
               
               
                 Nicotinamide 
                 A water soluble vitamin and 
                 122.12 
                 g/mol 
                 C 6 H 6 N 2 O 
               
               
                   
                 is part of the vitamin B 
               
               
                   
                 group. Treatment of patients 
               
               
                   
                 with inflammatory skin 
               
               
                   
                 conditions, and acts as a 
               
               
                   
                 chemo- and radiosensitizing 
               
               
                   
                 agent by enhancing tumor 
               
               
                   
                 blood flow. 
               
               
                 Methylthioninium 
                 Treats itch, and used as an 
                 319.85 
                 g/mol 
                 C 16 H 10 N 3 SCl 
               
               
                 Chloride 
                 antidote for cyanide 
               
               
                   
                 poisoning and as a bacterial stain. 
               
               
                 Diamox 
                 Treats conditions like 
                 222.245 
                 g/mol 
                 C 4 H 6 N 4 O 3 S 2   
               
               
                   
                 glaucoma, epileptic seizures, 
               
               
                   
                 hypertension, and altitude 
               
               
                   
                 sickness. 
               
               
                 Ipratropium 
                 An anticholingeric 
                 412.37 
                 g/mol 
                 C 20 H 30 BrNO 3   
               
               
                 bromide 
                 bronchodilator that blocks 
               
               
                   
                 muscarinic acetylcholine 
               
               
                   
                 receptors and opens bronchi. 
               
               
                 Clomipramine 
                 Blocks serotonin, 
                 314.9 
                 g/mol 
                 C 19 H 23 ClN 2   
               
               
                   
                 norepinephrine, and 
               
               
                   
                 dopamine transporters. Is an 
               
               
                   
                 antidepressant. 
               
               
                 Azathioprine 
                 Used to prevent the rejection 
                 277.263 
                 g/mol 
                 C 9 H 7 N 7 O 2 S 
               
               
                   
                 of kidney transplants. Also 
               
               
                   
                 used to treat rheumatoid 
               
               
                   
                 arthritis. Weakens the 
               
               
                   
                 body&#39;s immune system. 
               
               
                 Naloxone 
                 Treatment for opiate 
                 327.37 
                 g/mol 
                 C 19 H 21 NO 4   
               
               
                   
                 overdose. Also used in the 
               
               
                   
                 treatment of congenital 
               
               
                   
                 insensitivity to pain with 
               
               
                   
                 anhidrosis. 
               
               
                 Carbamazepine 
                 Treatment of seizures, 
                 236.269 
                 g/mol 
                 C 15 H 12 N 2 O 
               
               
                   
                 trigeminal neuralgia, mania, 
               
               
                   
                 and bipolar I disorder. 
               
               
                 Thiamine 
                 A water soluble vitamin of 
                 300.81 
                 g/mol 
                 C 12 ZH 17 N 4 OS 
               
               
                   
                 the B complex. Released by 
               
               
                   
                 the action of phosphatase 
               
               
                   
                 and pyrophosphatase in the 
               
               
                   
                 upper small intestine. 
               
               
                 Amitriptyline 
                 Treatment of depressive 
                 277.403 
                 g/mol 
                 C 20 H 23 N 
               
               
                   
                 disorders, anxiety disorders, 
               
               
                   
                 ADHD, migraine 
               
               
                   
                 prophylaxis, and many other 
               
               
                   
                 disorders. 
               
               
                 Salbutamol 
                 Adrenergic bronchodilator 
                 239.311 
                 g/mol 
                 C 13 H 21 NO 3   
               
               
                   
                 that opens bronchial tubes. 
               
               
                   
                 Prevents asthma, bronchitis, 
               
               
                   
                 emphysema, etc. 
               
               
                 Timoptol 
                 Treats high blood pressure, 
                 223.678 
                 g/mol 
                 C 13 H 24 N 4 O 3 S 
               
               
                   
                 to prevent hard attacks, 
               
               
                   
                 prevents migraines, and 
               
               
                   
                 treats open-angle and 
               
               
                   
                 secondary glaucoma. 
               
               
                 Caffeine Citrate 
                 Treats sever migraines. 
                 194.19 
                 g/mol 
                 C 4 H 5 N 2 O 
               
               
                   
                   
                   
                   
                 C 3 H 4 O 3   
               
               
                 Tropicamide 
                 Used to dilate the pupil and 
                 284.353 
                 g/mol 
                 C 17 H 20 N 2 O 2   
               
               
                   
                 better allows for the 
               
               
                   
                 examination of the lens, 
               
               
                   
                 vitreous humor and retina. 
               
               
                 Salagen 
                 Treats Sjogren&#39;s syndrome, 
                 208.257 
                 g/mol 
                 C 11 H 16 N 2 O 2   
               
               
                   
                 chronic open-angle 
               
               
                   
                 glaucoma and acute angle- 
               
               
                   
                 closure glaucoma. 
               
               
                 Atropine 
                 Lowers the parasympathetic 
                 289.369 
                 g/mol 
                 C 17 H 23 NO 3   
               
               
                   
                 activity of muscles and 
               
               
                   
                 glands. Used to temporarily 
               
               
                   
                 paralyze the accommodation 
               
               
                   
                 reflex and to dilate the 
               
               
                   
                 pupils. 
               
               
                 Morphine 
                 Opiate analgesic medication 
                 285.34 
                 g/mol 
                 C 17 H 19 NO 3   
               
               
                   
                 used to treat severe pain. 
               
               
                 Amidotrizoate 
                 Used in urography, 
                 613.91 
                 g/mol 
                 C 11 H 9 I 3 N 2 O 4   
               
               
                   
                 venography, operative 
               
               
                   
                 cholangiography, 
               
               
                   
                 splenoportography, 
               
               
                   
                 arthrography, discography 
               
               
                   
                 and computer-assisted axial 
               
               
                   
                 tomography. 
               
               
                 Hydrochlorothiazide 
                 Treats high blood pressure 
                 297.74 
                 g/mol 
                 C 7 H 8 ClN 3 O 4 S 2   
               
               
                   
                 and fluid retention. Also 
               
               
                   
                 used to prevent kidney 
               
               
                   
                 stones in patients with high 
               
               
                   
                 levels of calcium in their 
               
               
                   
                 blood. 
               
               
                 Deferoxamine 
                 Used to treat acute iron 
                 560.684 
                 g/mol 
                 C 25 H 48 N 6 O 8   
               
               
                   
                 poisoning, especially in 
               
               
                   
                 small children. Also used to 
               
               
                   
                 treat hemochromatosis. 
               
               
                 Chlorphenamine 
                 Treats allergy symptoms 
                 274.788 
                 g/mol 
                 C 16 H 19 ClN 2   
               
               
                   
                 such as those from hay 
               
               
                   
                 fever, hives, and runny nose. 
               
               
                 Riboflavin 
                 Easily absorbed 
                 376.36 
                 g/mol 
                 C 17 H 20 N 4 O 6   
               
               
                   
                 micronutrient with a key role 
               
               
                   
                 in maintaining health in 
               
               
                   
                 humans and animals, and is 
               
               
                   
                 required for a large number 
               
               
                   
                 of cellular processes. 
               
               
                 DL-Methionine 
                 Used to prevent liver 
                 149.21 
                 g/mol 
                 C 5 H 11 NO 2 S 
               
               
                   
                 damage in acetaminophen 
               
               
                   
                 poisoning. Also used to 
               
               
                   
                 increasing acidity of urine, 
               
               
                   
                 treating liver disorders, and 
               
               
                   
                 improving wound healing. 
               
               
                   
                 Treats depression, 
               
               
                   
                 alcoholism, allergies, 
               
               
                   
                 asthma, and many other 
               
               
                   
                 disorders. 
               
               
                 Setraline 
                 Antidepressant and is highly 
                 306.229 
                 g/mol 
                 C 17 H 17 Cl 2 N 
               
               
                   
                 effective for the treatment of 
               
               
                   
                 panic disorder. 
               
               
                 Acetylcysteine 
                 Helps loosen mucus in 
                 163.19 
                 g/mol 
                 C 5 H 9 NO 3 S 
               
               
                   
                 airways. Also helps prevent 
               
               
                   
                 liver damage from 
               
               
                   
                 acetaminophen overdose. 
               
               
                 Nifedipine 
                 Treats high blood pressure 
                 346.335 
                 g/mol 
                 C 17 H 18 N 2 O 6   
               
               
                   
                 and controls chest pains. 
               
               
                   
                 Increases blood supply to the 
               
               
                   
                 heart. 
               
               
                 Ganclovir 
                 An antiviral medication used 
                 225.23 
                 g/mol 
                 C 9 H 13 N 5 O 4   
               
               
                   
                 to treat CMV. It terminates 
               
               
                   
                 elongation of viral DNA. 
               
               
                 Tetracaine 
                 Local anesthetic of the ester 
                 264.363 
                 g/mol 
                 C 15 H 24 N 2 O 2   
               
               
                   
                 group. Alters the function of 
               
               
                   
                 calcium release channels. 
               
               
                 Ketamine 
                 Used for the induction and 
                 237.725 
                 g/mol 
                 C 13 H 16 ClNO 
               
               
                   
                 maintenance of general 
               
               
                   
                 anesthesia usually in 
               
               
                   
                 combination with a sedative. 
               
               
                 Bupivacaine 
                 Used for local anesthesia 
                 288.43 
                 g/mol 
                 C 18 H 16 N 2 O 
               
               
                   
                 including infiltration, nerve 
               
               
                   
                 block, epidural, and inrathel 
               
               
                   
                 calanesthesia. 
               
               
                 Paracetamol 
                 Relieves headaches and 
                 151.17 
                 g/mol 
                 C 8 H 9 NO 2   
               
               
                   
                 minor pains. 
               
               
                 Lidocaine 
                 A common local anesthetic 
                 234.34 
                 g/mol 
                 C 14 H 22 N 2 O 
               
               
                   
                 and antiarrhythmic drug. 
               
               
                   
                 Helps to relieve itching, 
               
               
                   
                 burning, and pain from skin 
               
               
                   
                 inflammation. 
               
               
                 Ephedrine 
                 Used as a stimulant, appetite 
                 165.23 
                 g/mol 
                 C 10 H 15 NO 
               
               
                   
                 suppressant, concentration 
               
               
                   
                 aid, decongestant, and to 
               
               
                   
                 treat hypertension associated 
               
               
                   
                 with anaesthesia. Also used 
               
               
                   
                 in the treatment of asthma, 
               
               
                   
                 bronchitis, and sea sickness. 
               
               
                 Thiopental 
                 Causes drowsiness or sleep 
                 205.678 
                 g/mol 
                 C 11 H 18 N 2 O 2   
               
               
                   
                 before surgery. Depresses 
               
               
                   
                 the central nervous system 
               
               
                   
                 and helps to stop seizures. 
               
               
                 Tetracycline 
                 A broad spectrum of 
                 444.435 
                 g/mol 
                 C 22 H 24 N 2 O 8   
               
               
                   
                 antibiotics that many 
               
               
                   
                 bacteria have developed 
               
               
                   
                 resistance to. Protein 
               
               
                   
                 inhibitors. 
               
               
                 Neostigmine 
                 Acts as a reversible 
                 223.294 
                 g/mol 
                 C 12 H 19 N 2 O 2   
               
               
                   
                 acetylcholinsterase inhibitor. 
               
               
                   
                 Stimulates nicotinic and 
               
               
                   
                 muscarinic receptors. 
               
               
                 Suxamethonium 
                 Used as a paralytic when 
                 290.399 
                 g/mol 
                 C 14 H 30 N 2 O 4   
               
               
                   
                 doing a tracheal intubation. 
               
               
                 Pyridostigmine 
                 Used to treat muscle 
                 181.212 
                 g/mol 
                 C 9 H 13 N 2 O 2   
               
               
                   
                 weakness in people with 
               
               
                   
                 myasthenia gravis. 
               
               
                   
               
            
           
         
       
     
     BRIEF SUMMARY OF DISCLOSURE 
     An object of the invention is to overcome the drawbacks relating to the compromise designs of prior art devices as discussed above. Copper ions in the form of singly charged and doubly charged ions have been well studied, toxicity of the copper cations against healthy and cancerous cells are well known and reported extensively in the scientific literature. 
     In this invention we revealed that binding copper to any amine containing drug can potentially improve its efficacy. The copper cation binding does this by three mechanisms (1) improved water solubility (2) adds rigidity to the structure to maximize ability to lock into a specific physiological target (3) by binding the amine, the pharmaceutical agent is less likely to bind to an unwanted site causing unwanted side effects. 
     This binding might be by hydrogen binding to a protein to cell wall; by an ion dipole interaction to a copper containing protein that contains central copper binding sites such as Copper B centre&#39;s (Cu B ), Type I copper centre&#39;s (T 1 Cu), Type II copper centre&#39;s (T 2 Cu), Type III copper centres (T 3 Cu), and Copper Z centre (Cu Z ). 
     This invention demonstrates that the copper cation does preferentially bind amines contained in the structures of the well-known medicinal agents taxol and quinine. Biological studies include the demonstration that binding taxol to iron (III) worsens the GI 50  values compared to uncomplexed taxol, while copper binding improves the GI 50  values compared to uncomplexed taxol. 
    
    
     DETAILED DESCRIPTION OF THE DISCLOSURE 
     Quinines neutral parent ion (Q 1 , C 20 H 24 N 2 O 2 ) has a mass of 324.183 Dalton (Da) for the most abundant isotopic species, the copper-quinine (Cu 1 C 20 H 24 N 2 O 2 ; CuQ 1 ) has a mass of 387.113 Da, the quinine dimer (C 40 H 48 N 4 O 4 ; Q 2 ) has a mass of 648.367 Da, and the copper (II) diquinine complex has a mass of 711.297 Da (CuQ 2 ; Cu 2 C 40 H 48 N 4 O 4 ). All masses are for the most prominent isotopic species. In mass spectral data these may appear as a (+H + ) or m−1 (−H + ) adducts.  63 Cu (69% natural abundance) and  65 Cu (31% natural abundance) are the stable isotopes of copper found in nature and provide a mass spectral pattern that is easily identified. Both Matrix Assisted Laser Desorption Ionization-Time of Flight-Mass Spectrometry (MALDI-TOF-MS) and liquid chromatography-mass spectrometry (LC-MS) were used to study the complex. With this complex, the MALDI-TOF-MS proved more useful. It revealed the presence of the parent ion (Q), CuQ 1 , CuQ 2  and Q 2  complexes. Mass spectral data for the CuQ 2  complex and the experimental evidence of the quinine dimer have been published by this group. In the copper complexes the cations&#39; unique isotopic pattern is evident in the mass spectra. 
     The quinine dimer (Q 2 ) was observed in the quinine and copper-quinine solutions. It indicates that the species can be linked without protons (m/z=648) and with amines protonated (m/z=650). The bond distances between the amines on one structure and the closest hydrogen&#39;s on the adjacent structure, coupled with the energy calculation, indicate a stable dimer structure. Table 2 and 3 provide the distances between two quinine molecules and between two quinine molecules in which the amines are protonated and linked by hydrogen bonds. 
     None of the mass spectrometry studies, MALDI-TOF-MS or LC-MS, indicated that chloride or water was trapped in the inner sphere of the copper-quinine complexes. Given that Copper(II) is hexavalent, this indicates that each quinine molecule in the CuQ 2  complex occupies three sites. There are six potential binding sites on each quinine molecule, the two amines (Cu—N), two oxygen (Cu—O), and two Cu-pi bonds from the ethylene and the aromatic ring. 
     Table 4 provides a summary of the  1 H and  13 C Nuclear Magnetic Resonance (NMR) for the quinine and CuQ 2  complex. The shifts in position 1 (C, H atoms) indicate that the methoxy group interacts with the copper(II) ion. The lack of shifting of the entire over six member ring (#2-6) indicates its pi bonds are not involved in the binding of the copper(II) ion. The shift in positions 9 but not in position 10 indicates the amine (N #1) is involved in binding Copper(II) but not the pi bonds in the aromatic structure. The shifts in positions 11, 12 and 14 indicate the —OH and the amine (N #2) have an interaction with the copper(II). The shifts in positions #15, 17, 18, 19, and 20, which are clearly not binding sites, have shifts in their line positions due to changes in the structural changes as the natural product sticks to the Ccopper(II) ion. The shifts in carbons #9, 11, 12, 14, and 17 between the quinine and the Cu-quinine NMR experiments indicate the Copper(II) binds the two amines and the oxygen atoms. The small shifts in carbons and hydrogen numbers 1, 2, and 4 indicate the cation binding does not shift the whole structure. The shifts in carbons and hydrogen&#39;s number 19 and 20 suggest an interaction between the cation and the pi bonds. The numbering system used has been outlined in our journal articles on this topic. 
     In addition to the shifts in position, the spectra metal-ligand complex shows significant broadening of the spectral features which can be attributed to a rapid exchange involving the Cu—O and Cu—N bonds. This exchange, which can involve solvent or salt species, has been studied by NMR for other species such as gadolinium (III) binding DTPA. These lanthanide-aminocarboxylate complexes have been studied in the solution phase extensively because of their role as Magnetic Resonance Imaging contrast reagents. For our complexes, the following equilibrium can be suggested from the NMR and MS data; 
       Cu 2+ (aq)+2Q(aq)   Cu(Q) 2   +1 (aq)K&gt;&gt;1  (4)
 
       Cu(Q) 2   +1 (aq)+H 2 O(1)   Cu(Q) 2   +1 (H 2 O) 1 (aq)K&lt;&lt;1  (5)
 
       Cu(Q) 2   +1 (aq)+Cl − (aq))   Cu(Q) 2 (Cl) 1 (aq)K&lt;&lt;1  (6)
 
       Q(aq)+Q(aq)   Q 2 (aq)K&gt;1  (7)
 
     When K, the equilibrium constant, is greater than 1 it indicates there is a detectable complex. With K&lt;1, we were not able to detect the complex. The mass spectrometer studies did not detect Cu(Q) 2   +1 (H 2 O) 1  or Cu(Q) 2 (Cl) 1 (aq) directly but the dynamic presence (water, chloride) in the inner sphere temporarily is suggested by the broadening of the peaks in the proton NMR experiments. Likewise, five potential binding sites on each quinine (2 Cu—N; 2 Cu—O; 1 Cu-pi/ethylene) but only three active coupled Copper(II)&#39;s octahedral geometry indicates that three sites per quinine are in dynamic equilibrium with the cation at any given moment. 
     In this application, we also reveal that attaching a known medicinal agent to a copper ion can not only be used to increase water solubility and stability but also change the geometry to match other molecular complexes that have higher medicinal values. As an example, we attach two quinine molecules to a single copper cation in order to build a complex that has a similar shape and size to vinblastine and vincristine. Vinblastine and vincristine are two well-known natural products that are used in treating different types of cancers. Larger molecules can be difficult to synthesize which limits their applications in the medical community. 
     Table 5 shows some calculated parameters including their dipole moment, molecular volume and molecular surface area. The complexes CuQ 1 ; CuQ 2  and CuQ 3  were also modeled using computational chemistry software. CuQ 2  (copper(II)-(quinine) 2   + ) was found to have a number of similarities in terms of chemical and physical parameters to vincristine and vinblastine. The CuQ 2  complex was synthesized in this lab and accepted for testing at the National Cancer Institute against its sixty cancer cell line panel. 
     Also of note, the malarial drug hydroxychloroquine has recently been shown to impact pancreatic cancer and is entering Phase I clinical trials. The National Cancer Institute&#39;s DTP program accepted the CuQ 2  complex for testing against its 60 cancer cell line panel. The average growth rate of the cancer cells treated with the CuQ 2  complex, measured in the single dose run, increased slightly (103.70%; +/−23.38) compared to the controls (see table 6 for results). This complex performed at a similar level compared to individual tests for copper(II) sulfate as well as quinine sulfate (NSC). The results of the NCI 60 cell line panel for vinblastine and vincristine can be found on-line using the NCI-DTP COMPARE website and search engine. 
     The copper (II) taxol complex has also been synthesized in this lab and evaluated by the National Cancer Institute against their 60 cell line panel and modeled extensively using computational software. Tables 7, 8, and 9 provides comparative results for the National Cancer Institute results of the taxol (pure), copper(II)-taxol, and iron(III)-taxol cell line data. Table 7 is a detailed analysis between the administration of the copper(II)-taxol complex and pure taxol; table 8 is a comparison of the administration of the iron(III)-taxol complex and pure taxol; and table 9 is a comparison between the administration of the copper(II)-taxol complex and the iron(III)-taxol complex. This data clearly shows that iron-taxol complex has lower/less medicinal activity than pure taxol or the copper-taxol complex. It also demonstrates that the copper(II)-taxol complex is superior to the pure taxol molecule in terms of anti-cancer activity. The data sets were selected by using the same concentration ranges over which the drugs were applied to the cancer cell lines (10 −4  to 10 −8  M). In terms of medicinal activity; the CuQ 2  results show that binding copper ion to any drug doesn&#39;t make it more toxic simply because of the presence of the copper ion. Binding the iron cation to taxol and measuring a decrease in the medicinal activity shows that simply attaching any cation does not increase the drugs toxicity. Binding the copper cation to taxol and demonstrating an improvement in the medicinal activity of the well-known cancer drug shows that the copper (II) cation is a good delivery agent for medicinal products. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Calculated distances between two unprotonated quinine 
               
               
                 molecules forming a dimer in a vacuum and different 
               
               
                 solvents. All distances are reported in Angstroms. 
               
            
           
           
               
               
            
               
                 Solvent 
                 Distances Between Atoms 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 vacuum 
                 (O2,H15) = 
                 (O2,H21) = 
                 (H21,O2) = 
                   
               
               
                   
                 2.714 
                 3.023 
                 1.724 
               
               
                 methylene 
                 (O1,H21) = 
                 (H12,O1) = 
                 (H16,N2) = 
               
               
                 chloride 
                 2.023 
                 3.183 
                 3.159 
               
               
                 ethanol 
                 (O2,H21) = 
                 (H21,O2) = 
                 (H14,O2) = 
                 (H11,N1) = 
               
               
                   
                 1.835 
                 3.011 
                 3.083 
                 3.193 
               
               
                 water 
                 (O2,H21) = 
                 (H13,O2) = 
                 (H21,O2) = 
                 (H1,N1) = 
               
               
                   
                 1.671 
                 2.616 
                 3.258 
                 3.140 
               
               
                 acetone 
                 (O2,H21) = 
                 (H21,O2) = 
                 (H1,O1) = 
                 (O1,H5) = 
               
               
                   
                 1.796 
                 3.104 
                 2.772 
                 2.892 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Calculated distances involving the protonated amines 
               
               
                 and hydrogen bonds in the quinine dimer. All calculated 
               
               
                 distances are reported in Angstroms. 
               
            
           
           
               
               
            
               
                 Solvent 
                 Distances Between Atoms 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 vacuum 
                 (O2,N2*) = 
                 (O2,H11) = 
                 (O1,H10) = 
                   
               
               
                   
                 1.747 
                 2.636 
                 2.661 
               
               
                 methylene 
                 (O2,N2*) = 
                 (O1,H21) = 
                 (O2,H78) = 
                 (H20,O1) = 
               
               
                 chloride 
                 1.876 
                 2.134 
                 2.978 
                 3.153 
               
               
                 ethanol 
                 (N1,H21) = 
                 (O2,N1*) = 
               
               
                   
                 2.289 
                 1.788 
               
               
                 water 
                 (O2,N2*) = 
                 (O2,H14) = 
                 (N2,H21) = 
                 (O1,H17) = 
               
               
                   
                 1.677 
                 3.212 
                 3.194 
                 2.892 
               
               
                 acetone 
                 (O1,N2*) = 
                 (H5,N2) = 
                 (O2,H17) = 
               
               
                   
                 1.847 
                 3.189 
                 2.567 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Experimental  13 C and  1 H NMR data for the 
               
               
                 quinine and the copper-quinine complexes. 
               
            
           
           
               
               
            
               
                 C 13  NMR Data 
                 H 1  NMR Data 
               
            
           
           
               
               
               
               
               
               
            
               
                 Carbon 
                 Quinine 
                 Cu-Quinine 
                 Proton 
                 Quinine 
                 Cu-Quinine 
               
               
                 (#) 
                 (ppm) 
                 (ppm) 
                 (#) 
                 (ppm) 
                 (ppm) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 1 
                 57.78 
                 56.03 
                 1 
                 3.9  
                 4.06 
               
               
                 2 
                 128.64 
                 127.18  
                 2 
                 7.35 
                 7.33 
               
               
                 3 
                 131.52 
                 * 
                 3 
                 7.96 
                 7.97 
               
               
                 4 
                 128.68 
                 127.18  
                 4 
                 — 
                 — 
               
               
                 5 
                 128.16 
                 * 
                 5 
                 7.41 
                 7.45 
               
               
                 6 
                 150.75 
                 * 
                 6 
                 — 
                 — 
               
               
                 7 
                 142.78 
                 * 
                 7 
                 — 
                 — 
               
               
                 8 
                 148.184 
                 * 
                 8 
                 — 
                 — 
               
               
                 9 
                 144.84 
                 138.06  
                 9 
                 8.6  
                 9.11 
               
               
                 10 
                 128.66 
                 127.18  
                 10 
                 7.65 
                 7.67 
               
               
                 11 
                 72.3 
                 66.82 
                 11 
                 4.87 
                 4.87 
               
               
                 12 
                 61.12 
                 59.96 
                 12 
                 2.22 
                 2.09 
               
               
                 13 
                 28.28 
                 23.53 
                 13 
                 1.69 
                 1.29 
               
               
                 14 
                 44.18 
                 43.27 
                 14 
                 3.01 
                 3.46 
               
               
                 15 
                 41.01 
                 36.57 
                 15 
                 1.83 
                 1.91 
               
               
                 16 
                 29.25 
                 26.93 
                 16 
                 1.49 
                 1.44 
               
               
                 17 
                 56.53 
                 54.06 
                 17 
                 2.59 
                 2.78 
               
               
                 18 
                 21.68 
                 18.01 
                 18 
                 1.35 
                 0.89 
               
               
                 19 
                 123.4 
                 * 
                 19 
                 5.6  
                 5.71 
               
               
                 20 
                 120.09 
                 115.51  
                 20 
                 4.85 
                 5.04 
               
               
                   
                   
                   
                 21 
                 0.71 
                 0.81 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Some calculated parameters for the Cu-quinine complexes as well as vinblastine and vincristine. 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Cu-quinine 
                 Cu-quinine 2   
                 Cu-quinine 3   
                 Cu-quinine 4   
                 vinblastine 
                 vincristine 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Emp. 
                 CuC 20 H 20 N 2 O 2   
                 CuC 40 H 40 N 4 O 4   
                 CuC 60 H 60 N 6 O 6   
                 CuC 80 H 80 N 8 O 8   
                 C 46 H 58 N 4 O 9   
                 C 46 H 56 N 4 O 10   
               
               
                 Form. 
               
               
                 molar 
                 393.01 
                 716.43 
                 1039.84 
                 1363.26 
                 810.99 
                 824.97 
               
               
                 mass 
               
               
                 surface 
                 397.02 
                 703.72 
                 975.15 
                 1410.04 
                 771.62 
                 764.48 
               
               
                 area (Å 2 ) 
               
               
                 volume 
                 381.28 
                 716.70 
                 1048.89 
                 1406.59 
                 810.53 
                 812.33 
               
               
                 (Å 3 ) 
               
               
                 dipole 
                 14.54 
                 4.43 
                 3.62 
                 3.00 
                 4.28 
                 4.37 
               
               
                 moment 
               
               
                 (Debye) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Results from the National Cancer Institute 60 
               
               
                 cell line cancer panel for the Cu-Q 2  complex. 
               
            
           
           
               
               
               
            
               
                 Panel Name 
                 Cell Panel Name 
                 Growth Percent 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Leukemia 
                 CCRF-CEM 
                 100.1026483 
               
               
                 Leukemia 
                 HL-60(TB) 
                 106.1784544 
               
               
                 Leukemia 
                 MOLT-4 
                 96.48688353 
               
               
                 Leukemia 
                 RPMI-8226 
                 105.770999 
               
               
                 Leukemia 
                 SR 
                 80.31978681 
               
               
                 Non-Small Cell Lung Cancer 
                 A549/ATCC 
                 88.42615546 
               
               
                 Non-Small Cell Lung Cancer 
                 EKVX 
                 119.2648546 
               
               
                 Non-Small Cell Lung Cancer 
                 HOP-62 
                 132.6766986 
               
               
                 Non-Small Cell Lung Cancer 
                 HOP-92 
                 88.14007268 
               
               
                 Non-Small Cell Lung Cancer 
                 NCI-H226 
                 103.6319613 
               
               
                 Non-Small Cell Lung Cancer 
                 NCI-H23 
                 104.3440424 
               
               
                 Non-Small Cell Lung Cancer 
                 NCI-H322M 
                 119.9117706 
               
               
                 Non-Small Cell Lung Cancer 
                 NCI-H460 
                 105.7854775 
               
               
                 Non-Small Cell Lung Cancer 
                 NCI-H522 
                 94.88939741 
               
               
                 Colon Cancer 
                 COLO 205 
                 91.74264468 
               
               
                 Colon Cancer 
                 HCC-2998 
                 108.9497649 
               
               
                 Colon Cancer 
                 HCT-116 
                 96.94777796 
               
               
                 Colon Cancer 
                 HCT-15 
                 98.35393057 
               
               
                 Colon Cancer 
                 HT29 
                 84.67973377 
               
               
                 Colon Cancer 
                 KM12 
                 91.03570637 
               
               
                 Colon Cancer 
                 SW-620 
                 111.0065851 
               
               
                 CNS Cancer 
                 SF-268 
                 125.3939346 
               
               
                 CNS Cancer 
                 SF-295 
                 85.69825167 
               
               
                 CNS Cancer 
                 SF-539 
                 102.385071 
               
               
                 CNS Cancer 
                 SNB-19 
                 108.7021707 
               
               
                 CNS Cancer 
                 SNB-75 
                 126.4355479 
               
               
                 CNS Cancer 
                 U251 
                 83.15718737 
               
               
                 Melanoma 
                 LOX IMVI 
                 80.60818436 
               
               
                 Melanoma 
                 MALME-3M 
                 105.6711816 
               
               
                 Melanoma 
                 M14 
                 101.0757053 
               
               
                 Melanoma 
                 MDA-MB-435 
                 91.46637969 
               
               
                 Melanoma 
                 SK-MEL-2 
                 95.23809524 
               
               
                 Melanoma 
                 SK-MEL-28 
                 109.1915262 
               
               
                 Melanoma 
                 UACC-257 
                 93.34409967 
               
               
                 Melanoma 
                 UACC-62 
                 84.77999268 
               
               
                 Ovarian Cancer 
                 IGROV1 
                 124.1484301 
               
               
                 Ovarian Cancer 
                 OVCAR-3 
                 119.951598 
               
               
                 Ovarian Cancer 
                 OVCAR-4 
                 110.3503826 
               
               
                 Ovarian Cancer 
                 OVCAR-5 
                 116.2155367 
               
               
                 Ovarian Cancer 
                 OVCAR-8 
                 103.7933704 
               
               
                 Ovarian Cancer 
                 NCI/ADR-RES 
                 104.9770339 
               
               
                 Ovarian Cancer 
                 SK-OV-3 
                 95.06726457 
               
               
                 Renal Cancer 
                 786-0 
                 120.528015 
               
               
                 Renal Cancer 
                 ACHN 
                 100.5583965 
               
               
                 Renal Cancer 
                 CAKI-1 
                 109.9162586 
               
               
                 Renal Cancer 
                 RXF 393 
                 139.8852435 
               
               
                 Renal Cancer 
                 SN12C 
                 109.4295115 
               
               
                 Renal Cancer 
                 TK-10 
                 114.9988654 
               
               
                 Renal Cancer 
                 UO-31 
                 92.23359422 
               
               
                 Prostate Cancer 
                 DU-145 
                 113.2964586 
               
               
                 Breast Cancer 
                 MCF7 
                 84.96834489 
               
               
                 Breast Cancer 
                 MDA-MB-231/ATCC 
                 82.35564757 
               
               
                 Breast Cancer 
                 HS 578T 
                 117.4853747 
               
               
                 Breast Cancer 
                 BT-549 
                 107.3682718 
               
               
                 Breast Cancer 
                 T-47D 
                 100.0629666 
               
               
                 Breast Cancer 
                 MDA-MB-468 
                 117.8457209 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 The average logGI 50  values (Molar) for the Copper(II)-taxol is 1.44544 times better than taxol 
               
               
                 or (1.44 − 1.00)/(1.0) * 100 = 44% better. Fifty-one of the copper-taxol were the same 
               
               
                 or better than pure taxol. Twenty-three of the cell lines have the same value. If both have same 
               
               
                 GI 50  value, copper(II)-taxol was selected because it has higher water solubility and more likely 
               
               
                 to perform better in animal/human trials. There are seven “missing data” because they did 
               
               
                 not have the same set of cell lines, and three of the pure taxol cell lines outperformed copper-taxol. 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 Copper(II)-Taxol 
                 Taxol 
                 Copper(II)-Taxol/ 
                   
               
               
                 Panel Name 
                 Line Name 
                 (logGI 50 ) 
                 (logGI 50 ) 
                 Taxol ratio 
                 Favored 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Average (10 x ) 
                 — 
                 −7.748 
                 −7.588 
                 0.69183 
                 Cutaxol 
               
               
                 Leukemia 
                 CCRF-CEM 
                 −8 
                 −8 
                 1 
                 Cutaxol 
               
               
                 Leukemia 
                 HL-60(TB) 
                 −8 
                 −8 
                 1 
                 Cutaxol 
               
               
                 Leukemia 
                 K-562 
                 −8 
                 −7.9 
                 0.79432 
                 Cutaxol 
               
               
                 Leukemia 
                 MOLT-4 
                 −8 
                 −7.8 
                 0.6309 
                 Cutaxol 
               
               
                 Leukemia 
                 RPMI-8226 
                 −8 
                 −8 
                 1 
                 Cutaxol 
               
               
                 Leukemia 
                 SR 
                 −8 
                 −7.5 
                 0.31622 
                 Cutaxol 
               
               
                 Non-Small Cell Lung 
                 A549/ATCC 
                 −8 
                 −7.98 
                 0.9549 
                 Cutaxol 
               
               
                 Non-Small Cell Lung 
                 EKVX 
                 −8 
                 −6.96 
                 0.0912 
                 Cutaxol 
               
               
                 Non-Small Cell Lung 
                 HOP-62 
                 −8 
                 −7.62 
                 0.4168 
                 Cutaxol 
               
               
                 Non-Small Cell Lung 
                 HOP-92 
                 −5.29 
                 −7.82 
                 338.84 
                 Taxol 
               
               
                 Non-Small Cell Lung 
                 NCI-H226 
                 −4.92 
                 −6.01 
                 12.302 
                 Taxol 
               
               
                 Non-Small Cell Lung 
                 NCI-H23 
                 −8 
                 −7.94 
                 0.8709 
                 Cutaxol 
               
               
                 Non-Small Cell Lung 
                 NCI-H322M 
                 −8 
                 −8 
                 1 
                 Cutaxol 
               
               
                 Non-Small Cell Lung 
                 NCI-H460 
                 −8 
                 −8 
                 1 
                 Cutaxol 
               
               
                 Non-Small Cell Lung 
                 NCI-H522 
                 −8 
                 −8 
                 1 
                 Cutaxol 
               
               
                 Colon 
                 COLO205 
                 −8 
                 −8 
                 1 
                 Cutaxol 
               
               
                 Colon 
                 HCC-2998 
                 −8 
                 −7.99 
                 0.9772 
                 Cutaxol 
               
               
                 Colon 
                 HCT-116 
                 −8 
                 −8 
                 1 
                 Cutaxol 
               
               
                 Colon 
                 HCT-15 
                 −6.53 
                 −6.54 
                 1.0232 
                 Taxol 
               
               
                 Colon 
                 HT29 
                 No Data 
                 −8 
                 No Data 
                 No Data 
               
               
                 Colon 
                 KM12 
                 −8 
                 −8 
                 1 
                 Cutaxol 
               
               
                 Colon 
                 SW-620 
                 −8 
                 −8 
                 1 
                 Cutaxol 
               
               
                 CNS 
                 SF-268 
                 −8 
                 −7.96 
                 0.91201 
                 Cutaxol 
               
               
                 CNS 
                 SF-295 
                 −8 
                 −7.83 
                 0.6760 
                 Cutaxol 
               
               
                 CNS 
                 SF-539 
                 −8 
                 −8 
                 1 
                 Cutaxol 
               
               
                 CNS 
                 SNB-19 
                 −8 
                 −7.94 
                 0.8709 
                 Cutaxol 
               
               
                 CNS 
                 SNB-75 
                 −8 
                 −8 
                 1 
                 Cutaxol 
               
               
                 CNS 
                 U251 
                 −8 
                 −8 
                 1 
                 Cutaxol 
               
               
                 Melanoma 
                 LOXIMVI 
                 −8 
                 −8 
                 1 
                 Cutaxol 
               
               
                 Melanoma 
                 MALME-3M 
                 No Data 
                 −6.34 
                 No Data 
                 No Data 
               
               
                 Melanoma 
                 M14 
                 −8 
                 −7.99 
                 0.97723 
                 Cutaxol 
               
               
                 Melanoma 
                 MDA-MB-435 
                 −8 
                 −7.89 
                 0.77624 
                 Cutaxol 
               
               
                 Melanoma 
                 SK-MEL-2 
                 No Data 
                 −8 
                 No Data 
                 No Data 
               
               
                 Melanoma 
                 SK-MEL-28 
                 −8 
                 −6.06 
                 0.01148 
                 Cutaxol 
               
               
                 Melanoma 
                 SK-MEL-5 
                 −8 
                 −8 
                 1 
                 Cutaxol 
               
               
                 Melanoma 
                 UACC-257 
                 −8 
                 −6.64 
                 0.04365 
                 Cutaxol 
               
               
                 Melanoma 
                 UACC-62 
                 −8 
                 −7.87 
                 0.74131 
                 Cutaxol 
               
               
                 Ovarian 
                 IGROV1 
                 −8 
                 −7.74 
                 0.54954 
                 Cutaxol 
               
               
                 Ovarian 
                 OVCAR-3 
                 −8 
                 −7.85 
                 0.70794 
                 Cutaxol 
               
               
                 Ovarian 
                 OVCAR-4 
                 −8 
                 −5.83 
                 0.0067 
                 Cutaxol 
               
               
                 Ovarian 
                 OVCAR-5 
                 −8 
                 −7.82 
                 0.66069 
                 Cutaxol 
               
               
                 Ovarian 
                 OVCAR-8 
                 −8 
                 −8 
                 1 
                 Cutaxol 
               
               
                 Ovarian 
                 NCI/ADR-RES 
                 −5.86 
                 −5.72 
                 0.7244 
                 Cutaxol 
               
               
                 Ovarian 
                 SK-OV-3 
                 −8 
                 −7.95 
                 0.89125 
                 Cutaxol 
               
               
                 Renal 
                 786-0 
                 No Data 
                 −7.59 
                 No Data 
                 No Data 
               
               
                 Renal 
                 A498 
                 −8 
                 −8 
                 1 
                 Cutaxol 
               
               
                 Renal 
                 ACHN 
                 −6.41 
                 −6.02 
                 0.40738 
                 Cutaxol 
               
               
                 Renal 
                 CAKI-1 
                 −7.25 
                 −6.5 
                 0.17782 
                 Cutaxol 
               
               
                 Renal 
                 RXF393 
                 −8 
                 −8 
                 1 
                 Cutaxol 
               
               
                 Renal 
                 SN12C 
                 −8 
                 −7.2 
                 0.15848 
                 Cutaxol 
               
               
                 Renal 
                 TK-10 
                 −7.49 
                 −7.03 
                 0.3467 
                 Cutaxol 
               
               
                 Renal 
                 UO-31 
                 −6.65 
                 −6.43 
                 0.60255 
                 Cutaxol 
               
               
                 Prostate 
                 PC-3 
                 No Data 
                 −8 
                 No Data 
                 No Data 
               
               
                 Prostate 
                 DU-145 
                 −8 
                 −8 
                 1 
                 Cutaxol 
               
               
                 Breast 
                 MCF7 
                 −8 
                 −8 
                 1 
                 Cutaxol 
               
               
                 Breast 
                 MDA-MB-231/ATCC 
                 −8 
                 −8 
                 1 
                 Cutaxol 
               
               
                 Breast 
                 HS578T 
                 −8 
                 −8 
                 1 
                 Cutaxol 
               
               
                 Breast 
                 MDA-N 
                 No Data 
                 −8 
                 No Data 
                 No Data 
               
               
                 Breast 
                 BT-549 
                 −8 
                 −7.9 
                 0.79432 
                 Cutaxol 
               
               
                 Breast 
                 T-47D 
                 No Data 
                 −7.06 
                 No Data 
                 No Data 
               
               
                 Breast 
                 MDA-MB-468 
                 −8 
                 −8 
                 1 
                 Cutaxol 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Pure taxol is 10.5 times better than the iron-taxol complex in the National 
               
               
                 cancer Institute 60 cel line trials. In only two cases does the iron-taxol complex 
               
               
                 have a more favorable logGI 50  value than pure taxol. 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                 FERRIC- 
                 Taxol/ 
                   
               
               
                   
                   
                 Taxol 
                 TAXOL 
                 Fe-taxol 
               
               
                 Panel Name 
                 Line Name 
                 (logGI 50 ) 
                 (logGI 50 ) 
                 ratio 
                 Favored 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Average 
                 — 
                 −7.588 
                  −6.566 
                 0.09506 
                 TAXOL 
               
               
                 Panel Name 
                 Line Name 
                 logGI 50   
                 logGI 50   
                 1 
                 TAXOL 
               
               
                 Leukemia 
                 CCRF-CEM 
                 −8 
                 −6.06 
                 0.01148 
                 TAXOL 
               
               
                 Leukemia 
                 HL-60(TB) 
                 −8 
                 No Data 
                   
                 No data 
               
               
                 Leukemia 
                 K-562 
                 −7.9 
                 −7.01 
                 0.12882 
                 TAXOL 
               
               
                 Leukemia 
                 MOLT-4 
                 −7.8 
                 −4.86 
                 0.00114 
                 TAXOL 
               
               
                 Leukemia 
                 RPMI-8226 
                 −8 
                 −7.13 
                 0.13489 
                 TAXOL 
               
               
                 Leukemia 
                 SR 
                 −7.5 
                 −6.7  
                 0.15848 
                 TAXOL 
               
               
                 Non-Small Cell Lung 
                 A549/ATCC 
                 −7.98 
                 −7.07 
                 0.1230 
                 TAXOL 
               
               
                 Non-Small Cell Lung 
                 EKVX 
                 −6.96 
                 −5.71 
                 0.05623 
                 TAXOL 
               
               
                 Non-Small Cell Lung 
                 HOP-62 
                 −7.62 
                 −4.91 
                 0.00194 
                 TAXOL 
               
               
                 Non-Small Cell Lung 
                 HOP-92 
                 −7.82 
                 −4.98 
                 0.0014 
                 TAXOL 
               
               
                 Non-Small Cell Lung 
                 NCI-H226 
                 −6.01 
                 −6.12 
                 1.28824 
                 No data 
               
               
                 Non-Small Cell Lung 
                 NCI-H23 
                 −7.94 
                 −6.79 
                 0.07079 
                 TAXOL 
               
               
                 Non-Small Cell Lung 
                 NCI-H322M 
                 −8 
                 −6.48 
                 0.03019 
                 TAXOL 
               
               
                 Non-Small Cell Lung 
                 NCI-H460 
                 −8 
                 −7.3  
                 0.19952 
                 TAXOL 
               
               
                 Non-Small Cell Lung 
                 NCI-H522 
                 −8 
                 −7.41 
                 0.25703 
                 TAXOL 
               
               
                 Colon 
                 COLO205 
                 −8 
                 −7.36 
                 0.22908 
                 TAXOL 
               
               
                 Colon 
                 HCC-2998 
                 −7.99 
                 −6.82 
                 0.06760 
                 TAXOL 
               
               
                 Colon 
                 HCT-116 
                 −8 
                 −7.41 
                 0.25703 
                 TAXOL 
               
               
                 Colon 
                 HCT-15 
                 −6.54 
                 −5.63 
                 0.12302 
                 TAXOL 
               
               
                 Colon 
                 HT29 
                 −8 
                 −7.48 
                 0.30199 
                 TAXOL 
               
               
                 Colon 
                 KM12 
                 −8 
                 −7.2  
                 0.15848 
                 TAXOL 
               
               
                 Colon 
                 SW-620 
                 −8 
                 −7.18 
                 0.15135 
                 TAXOL 
               
               
                 CNS 
                 SF-268 
                 −7.96 
                 −6.78 
                 0.06606 
                 TAXOL 
               
               
                 CNS 
                 SF-295 
                 −7.83 
                 −7.08 
                 0.17782 
                 TAXOL 
               
               
                 CNS 
                 SF-539 
                 −8 
                 −7.28 
                 0.19054 
                 TAXOL 
               
               
                 CNS 
                 SNB-19 
                 −7.94 
                 −6.27 
                 0.02137 
                 TAXOL 
               
               
                 CNS 
                 SNB-75 
                 −8 
                 −7.64 
                 0.43651 
                 TAXOL 
               
               
                 CNS 
                 U251 
                 −8 
                 −7.19 
                 0.15488 
                 TAXOL 
               
               
                 Melanoma 
                 LOXIMVI 
                 −8 
                 −6.97 
                 0.0933 
                 TAXOL 
               
               
                 Melanoma 
                 MALME-3M 
                 −6.34 
                 No Data 
                   
                 No data 
               
               
                 Melanoma 
                 M14 
                 −7.99 
                 −7.2  
                 0.1621 
                 TAXOL 
               
               
                 Melanoma 
                 MDA-MB-435 
                 −7.89 
                 −7.75 
                 0.7244 
                 TAXOL 
               
               
                 Melanoma 
                 SK-MEL-2 
                 −8 
                 −6.79 
                 0.0616 
                 TAXOL 
               
               
                 Melanoma 
                 SK-MEL-28 
                 −6.06 
                 −4.88 
                 0.06606 
                 TAXOL 
               
               
                 Melanoma 
                 SK-MEL-5 
                 −8 
                 −7.17 
                 0.14791 
                 TAXOL 
               
               
                 Melanoma 
                 UACC-257 
                 −6.64 
                 −4.74 
                 0.01258 
                 TAXOL 
               
               
                 Melanoma 
                 UACC-62 
                 −7.87 
                 −7.06 
                 0.15488 
                 TAXOL 
               
               
                 Ovarian 
                 IGROV1 
                 −7.74 
                 −6.68 
                 0.08709 
                 TAXOL 
               
               
                 Ovarian 
                 OVCAR-3 
                 −7.85 
                 −7.36 
                 0.32359 
                 TAXOL 
               
               
                 Ovarian 
                 OVCAR-4 
                 −5.83 
                 −6.14 
                 2.04173 
                 Ferric_Taxol 
               
               
                 Ovarian 
                 OVCAR-5 
                 −7.82 
                 −6.06 
                 0.01737 
                 TAXOL 
               
               
                 Ovarian 
                 OVCAR-8 
                 −8 
                 −7.14 
                 0.13803 
                 TAXOL 
               
               
                 Ovarian 
                 NCI/ADR-RES 
                 −5.72 
                 −4.72 
                 0.1 
                 TAXOL 
               
               
                 Ovarian 
                 SK-OV-3 
                 −7.95 
                 −6.85 
                 0.07943 
                 TAXOL 
               
               
                 Renal 
                 786-0 
                 −7.59 
                 −5.65 
                 0.01148 
                 TAXOL 
               
               
                 Renal 
                 A498 
                 −8 
                 −6.23 
                 0.01698 
                 TAXOL 
               
               
                 Renal 
                 ACHN 
                 −6.02 
                 −5.53 
                 0.32359 
                 TAXOL 
               
               
                 Renal 
                 CAKI-1 
                 −6.5 
                 −5.45 
                 0.08912 
                 TAXOL 
               
               
                 Renal 
                 RXF393 
                 −8 
                 −7.02 
                 0.10471 
                 TAXOL 
               
               
                 Renal 
                 SN12C 
                 −7.2 
                 −6.66 
                 0.2884 
                 TAXOL 
               
               
                 Renal 
                 TK-10 
                 −7.03 
                 −6.18 
                 0.14125 
                 TAXOL 
               
               
                 Renal 
                 UO-31 
                 −6.43 
                 −5.31 
                 0.0758 
                 TAXOL 
               
               
                 Prostate 
                 PC-3 
                 −8 
                 −6.66 
                 0.04570 
                 TAXOL 
               
               
                 Prostate 
                 DU-145 
                 −8 
                 −7.22 
                 0.16595 
                 TAXOL 
               
               
                 Breast 
                 MCF7 
                 −8 
                 −7.5  
                 0.31622 
                 TAXOL 
               
               
                 Breast 
                 MDA-MB-231/ATCC 
                 −8 
                 −6.14 
                 0.01380 
                 TAXOL 
               
               
                 Breast 
                 HS578T 
                 −8 
                 −6.85 
                 0.07079 
                 TAXOL 
               
               
                 Breast 
                 MDA-N 
                 −8 
                 No Data 
                   
                 No Data 
               
               
                 Breast 
                 BT-549 
                 −7.9 
                 −6.51 
                 0.04073 
                 TAXOL 
               
               
                 Breast 
                 T-47D 
                 −7.06 
                 −7.13 
                 1.17489 
                 Ferric_Taxol 
               
               
                 Breast 
                 MDA-MB-468 
                 −8 
                 −7.44 
                 0.275422 
                 TAXOL 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 The copper-taxol complex outperforms the iron-taxol complex by 15.205 times 
               
               
                 when comparing the GI 50  values measured in the NCI&#39;s 60 cell line. 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 CU-TAXOL. 
                 FE-TAXOL 
                 CuTax/ 
                   
               
               
                   
                   
                 CAS#1704487 
                 CAS#302203 
                 FeTax 
               
               
                 Panel Name 
                 Line Name 
                 (logGI 50 ) 
                 (logGI 50 ) 
                 ratio 
                 Favored 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Average 
                 — 
                 −7.748 
                  −6.566 
                 0.065765784 
                 Cu-tax 
               
               
                 Leukemia 
                 CCRF-CEM 
                 −8 
                 −6.06 
                 0.011481536 
                 Cutax 
               
               
                 Leukemia 
                 HL-60(TB) 
                 −8 
                 No Data 
                 No Data 
                 No data 
               
               
                 Leukemia 
                 K-562 
                 −8 
                 −7.01 
                 0.102329299 
                 Cutax 
               
               
                 Leukemia 
                 MOLT-4 
                 −8 
                 −4.86 
                 0.000724436 
                 Cutax 
               
               
                 Leukemia 
                 RPMI-8226 
                 −8 
                 −7.13 
                 0.134896288 
                 Cutax 
               
               
                 Leukemia 
                 SR 
                 −8 
                 −6.7  
                 0.050118723 
                 Cutax 
               
               
                 Non- Small Lung Cancer 
                 A549/ATCC 
                 −8 
                 −7.07 
                 0.117489755 
                 Cutax 
               
               
                 Non- Small Lung Cancer 
                 EKVX 
                 −8 
                 −5.71 
                 0.005128614 
                 Cutax 
               
               
                 Non- Small Lung Cancer 
                 HOP-62 
                 −8 
                 −4.91 
                 0.000812831 
                 Cutax 
               
               
                 Non- Small Lung Cancer 
                 HOP-92 
                 −5.29 
                 −4.98 
                 0.489778819 
                 Cutax 
               
               
                 Non- Small Lung Cancer 
                 NCI-H226 
                 −4.92 
                 −6.12 
                 15.84893192  
                 FeTax 
               
               
                 Non- Small Lung Cancer 
                 NCI-H23 
                 −8 
                 −6.79 
                 0.0616595  
                 Cutax 
               
               
                 Non- Small Lung Cancer 
                 NCI-H322M 
                 −8 
                 −6.48 
                 0.030199517 
                 Cutax 
               
               
                 Non- Small Lung Cancer 
                 NCI-H460 
                 −8 
                 −7.3  
                 0.199526231 
                 Cutax 
               
               
                 Non- Small Lung Cancer 
                 NCI-H522 
                 −8 
                 −7.41 
                 0.257039578 
                 Cutax 
               
               
                 Colon 
                 COLO205 
                 −8 
                 −7.36 
                 0.229086765 
                 Cutax 
               
               
                 Colon 
                 HCC-2998 
                 −8 
                 −6.82 
                 0.066069345 
                 Cutax 
               
               
                 Colon 
                 HCT-116 
                 −8 
                 −7.41 
                 0.257039578 
                 Cutax 
               
               
                 Colon 
                 HCT-15 
                 −6.53 
                 −5.63 
                 0.125892541 
                 Cutax 
               
               
                 Colon 
                 HT29 
                 No Data 
                 −7.48 
                 No data 
                 No data 
               
               
                 Colon 
                 KM12 
                 −8 
                 −7.2  
                 0.158489319 
                 Cutax 
               
               
                 Colon 
                 SW-620 
                 −8 
                 −7.18 
                 0.151356125 
                 Cutax 
               
               
                 CNS 
                 SF-268 
                 −8 
                 −6.78 
                 0.060255959 
                 Cutax 
               
               
                 CNS 
                 SF-295 
                 −8 
                 −7.08 
                 0.120226443 
                 Cutax 
               
               
                 CNS 
                 SF-539 
                 −8 
                 −7.28 
                 0.190546072 
                 Cutax 
               
               
                 CNS 
                 SNB-19 
                 −8 
                 −6.27 
                 0.018620871 
                 Cutax 
               
               
                 CNS 
                 SNB-75 
                 −8 
                 −7.64 
                 0.436515832 
                 Cutax 
               
               
                 CNS 
                 U251 
                 −8 
                 −7.19 
                 0.154881662 
                 Cutax 
               
               
                 Melanoma 
                 LOXIMVI 
                 −8 
                 −6.97 
                 0.09332543  
                 Cutax 
               
               
                 Melanoma 
                 M14 
                 −8 
                 −7.2  
                 0.158489319 
                 Cutax 
               
               
                 Melanoma 
                 MDA-MB-435 
                 −8 
                 −7.75 
                 0.562341325 
                 Cutax 
               
               
                 Melanoma 
                 SK-MEL-2 
                 No Data 
                 −6.79 
                 No data 
                 No data 
               
               
                 Melanoma 
                 SK-MEL-28 
                 −8 
                 −4.88 
                 0.000758578 
                 Cutax 
               
               
                 Melanoma 
                 SK-MEL-5 
                 −8 
                 −7.17 
                 0.147910839 
                 Cutax 
               
               
                 Melanoma 
                 UACC-257 
                 −8 
                 −4.74 
                 0.000549541 
                 Cutax 
               
               
                 Melanoma 
                 UACC-62 
                 −8 
                 −7.06 
                 0.114815362 
                 Cutax 
               
               
                 Ovarian 
                 IGROV1 
                 −8 
                 −6.68 
                 0.047863009 
                 Cutax 
               
               
                 Ovarian 
                 OVCAR-3 
                 −8 
                 −7.36 
                 0.229086765 
                 Cutax 
               
               
                 Ovarian 
                 OVCAR-4 
                 −8 
                 −6.14 
                 0.013803843 
                 Cutax 
               
               
                 Ovarian 
                 OVCAR-5 
                 −8 
                 −6.06 
                 0.011481536 
                 Cutax 
               
               
                 Ovarian 
                 OVCAR-8 
                 −8 
                 −7.14 
                 0.138038426 
                 Cutax 
               
               
                 Ovarian 
                 NCI/ADR-RES 
                 −5.86 
                 −4.72 
                 0.072443596 
                 Cutax 
               
               
                 Ovarian 
                 SK-OV-3 
                 −8 
                 −6.85 
                 0.070794578 
                 Cutax 
               
               
                 Renal 
                 786-0 
                 NoData 
                 −5.65 
                   
                 no data 
               
               
                 Renal 
                 A498 
                 −8 
                 −6.23 
                 0.016982437 
                 Cutax 
               
               
                 Renal 
                 ACHN 
                 −6.41 
                 −5.53 
                 0.131825674 
                 Cutax 
               
               
                 Renal 
                 CAKI-1 
                 −7.25 
                 −5.45 
                 0.015848932 
                 Cutax 
               
               
                 Renal 
                 RXF393 
                 −8 
                 −7.02 
                 0.104712855 
                 Cutax 
               
               
                 Renal 
                 SN12C 
                 −8 
                 −6.66 
                 0.045708819 
                 Cutax 
               
               
                 Renal 
                 TK-10 
                 −7.49 
                 −6.18 
                 0.048977882 
                 Cutax 
               
               
                 Renal 
                 UO-31 
                 −6.65 
                 −5.31 
                 0.045708819 
                 Cutax 
               
               
                 Prostate 
                 PC-3 
                 NoData 
                 −6.66 
                   
                 no data 
               
               
                 Prostate 
                 DU-145 
                 −8 
                 −7.22 
                 0.165958691 
                 Cutax 
               
               
                 Breast 
                 MCF7 
                 −8 
                 −7.5  
                 0.316227766 
                 Cutax 
               
               
                 Breast 
                 MDA-MB-231/ATCC 
                 −8 
                 −6.14 
                 0.013803843 
                 Cutax 
               
               
                 Breast 
                 HS578T 
                 −8 
                 −6.85 
                 0.070794578 
                 Cutax 
               
               
                 Breast 
                 BT-549 
                 −8 
                 −6.51 
                 0.032359366 
                 Cutax 
               
               
                 Breast 
                 T-47D 
                 NoData 
                 −7.13 
                   
                 no data 
               
               
                 Breast 
                 MDA-MB-468 
                 −8 
                 −7.44 
                 0.27542287  
                 Cutax 
               
               
                   
               
            
           
         
       
     
     Extensive work using proton and carbon nuclear magnetic resonance, time-of-flight mass spectrometry, liquid chromatography-mass spectrometry and Fourier transform-infrared spectrometry were used to experimental characterize the copper-taxol complex. It was deemed important to establish that the copper ion actually bound the taxol molecule at the single amine, a component of the molecule that is deemed structurally less important than other molecular areas in terms of the molecules structures anti-cancer activity. 
     The use of NMR for the isotopes  1 H,  13 C and  15 N are essential to deduce the structure of the copper-taxol complex. Table 10 provides a summary of the experimental and literature values for the proton ( 1 H) and  13 C NMR data. Some representative spectra are shown in this presentation to outline how the claim that copper (II) has an affinity for the amine is justified experimentally. 
     The copper-taxol complex&#39;s proton nuclear magnetic resonance spectra data demonstrated shifts in the spectra features of the pure taxol when compared to those of the copper (II)-taxol complex. This was important in establishing the copper ion did in fact bind the nitrogen atom. 
     A series of N 15  Nuclear Magnetic Resonance spectra was measured for pure taxol and for the copper-taxol complex. The pure taxol showed two spectral peaks for the pure taxol compound indicating it had two geometries in solution. The N 15  NMR spectra for the copper-taxol complex showed only a single spectral feature indicating a single geometry in solution. An analogy to this would be the well-known boat and chair geometries observed for aromatics (92 geometries), copper-taxol assumes only one of these geometries. 
     The N 15  NMR data is important for this invention describing the utilization of the copper cation as a delivery agent for pharmaceutical agents for two reasons. First, it indicates that the copper(II) ion is in fact binding taxol at the amine. Proposing that the copper (II) ion can serve as a delivery agent to amine-containing drugs must be supported by evidence that the copper (II) binds the amine with some high rate of selectivity. Second, the cancer cell line data presented above shows that the copper (II)-taxol complexed performed better than uncomplexed taxol in the National Cancer Institute&#39;s 60 cancer cell line panel. The taxol complex has two geometries as indicated by the two spectral features in the N 15  NMR. The copper (II) complex has one spectral feature indicating a single structure. Given the medicinal activity of taxol increases with the single geometry, this indicates that that geometry has more anti-cancer activity than the uncomplexed taxol. In addition to increasing water solubility, the copper (II) cation locks taxol into a single confirmation that has a preferred medicinal activity. 
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 Carbon-13 and Proton NMR data for taxol and copper (II) taxol complex are listed. 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   13 C Cu- 
                   
                   
                   1 H Cu- 
               
               
                 Assignment 
                   13 C Paper a   
                   13 C Taxol b   
                 Taxol b   
                   1 H Paper a   
                   1 H Taxol b   
                 Taxol b   
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Arom 1 
                 o 
                 130.2 
                 o 
                 131.504 
                 o 
                 — 
                 o 
                 8.13 
                 o 
                 8.11743 
                 o 
                 8.0437 
               
               
                   
                 m 
                 128.7 
                 m 
                 120.39 
                 m 
                 129.708 
                 m 
                 7.51 
                 m 
                 7.59447 
                 m 
                 7.5139 
               
               
                   
                 p 
                 133.7 
                 p 
                 134.1 
                 p 
                 133.492 
                 p 
                 7.61 
                 p 
                 7.69707 
                 p 
                 7.60814 
               
               
                 Arom 2 
                 o 
                 127.04 
                 o 
                 127.617 
                 o 
                 127.034 
                 o 
                 7.48 
                 o 
                 7.49583 
                 o 
                 7.48069 
               
               
                   
                 m 
                 129.0 
                 m 
                 128.35 
                 m 
                 128.121 
                 m 
                 7.42 
                 m 
                 7.30198 
                 m 
                 7.42014 
               
               
                   
                 p 
                 131.9 
                 p 
                 — 
                 p 
                 — 
                 p 
                 7.35 
                 p 
                 7.30393 
                 p 
                 7.34104 
               
               
                 Arom 3 
                 o 
                 127.04 
                 o 
                 127.11 
                 o 
                   
                 o 
                 7.74 
                 o 
                 7.8811 
                 o 
                 7.78978 
               
               
                   
                 m 
                 129.0 
                 m 
                 129.773 
                 m 
                 129.708 
                 m 
                 7.40 
                 m 
                 — 
                 m 
                 7.40012 
               
               
                   
                 p 
                 128.3 
                 p 
                 128.2 
                 p 
                 128.117 
                 p 
                 7.45 
                 p 
                 — 
                 p 
                 7.43626 
               
            
           
           
               
               
               
               
               
               
               
            
               
                  1′ 
                 172.7 
                 173.085 
                 172.975 
                 — 
                 — 
                 — 
               
               
                  2′ 
                 73.2 
                 — 
                 73.4403 
                 3.61 
                 3.50693 
                 3.76030 
               
               
                  3′ 
                 55.0 
                 — 
                 56.2854 
                 5.78 
                 5.66862 
                 — 
               
               
                  1 
                 79.0 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                  2 
                 74.9 
                 — 
                 — 
                 5.67 
                 5.6495 
                 5.58415 
               
               
                  3 
                 45.6 
                 — 
                 46.4243 
                 3.79 
                 3.83311 
                 3.77452 
               
               
                  4 
                 81.01 
                 — 
                 80.8409 
                 — 
                 — 
                 — 
               
               
                  5 
                 84.4 
                 — 
                 84.4039 
                 4.94 
                 4.90248 
                 4.80629 
               
               
                  6 
                 35.6 
                 — 
                 35.1479 
                 1.88 
                 1.83061 
                 1.85502 
               
               
                  7 
                 72.2 
                 — 
                 — 
                 4.40 
                 4.61585 
                 4.68714 
               
               
                  8 
                 58.6 
                 — 
                 57.7998 
                 — 
                 — 
                 — 
               
               
                  9 
                 203.6 
                 203.8 
                 203.653 
                 — 
                 — 
                 — 
               
               
                 10 
                 75.5 
                 — 
                 75.340 
                 6.27 
                 6.47 
                 6.38935 
               
               
                 11 
                 133.2 
                 133.267 
                 — 
                 — 
                 — 
                 — 
               
               
                 12 
                 142.0 
                 140.623 
                 — 
                 — 
                 — 
                 — 
               
               
                 13 
                 72.3 
                 — 
                 — 
                 6.23 
                 6.1745 
                 6.10321 
               
               
                 14 
                 35.7 
                 — 
                 36.0481 
                 2.28 
                 2.27447 
                 2.30377 
               
               
                 15 
                 43.2 
                 — 
                 43.1359 
                 — 
                 — 
                 — 
               
               
                 16 
                 21.8 
                 — 
                 21.7734 
                 1.14 
                 1.17189 
                 1.13918 
               
               
                 17 
                 26.9 
                 — 
                 25.447 
                 1.24 
                 −1.80522 
                 1.22317 
               
               
                 18 
                 14.8 
                 — 
                 — 
                 1.79 
                 1.67777 
                 1.75248 
               
               
                 19 
                 9.5 
                 — 
                 8.9852 
                 1.68 
                 4.20959 
                 1.60404 
               
               
                 20 
                 76.5 
                 — 
                 76.0267 
                 4.19 
                 — 
                 4.13635 
               
               
                 N—H (just 
                 — 
                 — 
                 — 
                 7.01 
                 — 
                 — 
               
               
                 H) 
               
               
                 O ac  (Top) 
                 170.4 
                 — 
                 — 
                 2.23 
                 2.19146 
                 2.11138 
               
               
                 O ac   
                 171.2 
                 170.035 
                 — 
                 2.38 
                 2.38189 
                 2.39215 
               
               
                 (Bottom) 
               
               
                 OH (Top) 
                 167.02 
                 166.318 
                 168.839 
                 2.48 
                 2.48883 
                 2.40631 
               
               
                 OH 
                 167.00 
                 168.9 
                 166.173 
                 1.98 
                 1.92973 
                 1.92924 
               
               
                 (Bottom) 
               
               
                   
               
               
                   a NMR data that appears in the scientific literature. 
               
               
                   b Experimental data acquired using a 500 MHz NMR. 
               
               
                   c o = ortho; m = meta; p = para 
               
            
           
         
       
     
     In order to better understand the interaction between the copper (II) cation and the medicinal agent taxol, a prototype example of an amine containing medicinal agent, well established computational methods are employed. In addition to demonstrating an increase in water solubility as evidence by an increase in charge, a shift in dipole moment is also shown as the preference of the copper (II) cation for the nitrogen atom. 
     To enhance and better understand this discovery, a computer based study involving 126 copper(II)-taxol complexes, 126 monohydrated copper-taxol-H 2 O complexes, and 2 basic taxol structures were computationally constructed. We evaluated a total of two hundred and fifty four molecules for this analysis. Experimental data indicates the copper (II) ion forms a hexavalent, octahedral geometry. Chelating compounds primarily form bonds with metal atoms by forming M*-O, or M*-N bonds. Copper specifically has a high affinity for amines. Considering these properties, all copper complexes were formed with a Cu—N bond and 5 Cu—O bonds. Given the molecular formula of taxol, (C 47 H 51 NO 14 ) and assuming that a Cu—N bond is present in all molecules, a permutations equation can be used to derive the total number of possible copper-taxol complexes (Table 11, 12). 
     For copper-taxol complexes there are a total of over two-thousand (2002) possible Cu—O and Cu—N bond combinations employing a hexavalent geometry, and for Cu-taxol-H 2 O complex there are over one thousand (1001) possible bonding combinations with a hexavalent geometry. These combinations assume that all oxygen atoms in the taxol molecule are available for bonding to the copper (II) ion. In this study, taxol analogues (breaking a bond in the taxol molecule to form a new bond with the cation) are not considered, thus reducing the number of possible oxygen atoms for bonding from 14 to 9. This results in 126 possible copper(II)-taxol complexes, and 126 possible copper-taxol-H 2 O complexes. Of the 252 possible combinations (126=126), those that had any Cu—O or Cu—N bond distances greater than 2.9 Å after performed calculations were eliminated as these bonds can be considered to be too long and lack covalence. The long bonds indicate a weak bond and would result in a weak complex, which is likely to dissociate. 
     The remaining molecules were used to generate tables 13 and 14. Of the 126 possible copper(II)-taxol complexes, four were shown to match the criteria set forth above, and these structures are summarized in table 13 along with the two taxol complexes included in this study. Of the 126 possible copper-taxol-H 2 O complexes, 16 were shown to match the criteria set forth above, and they are shown in table 14. With the hexavalent copper, the computational studies indicate zero or one of the six inner sphere sites can be occupied by water while the rest are occupied by a single nitrogen (amine) and oxygen atoms on the taxol structure. Given that experimental results do not show any waters in the inner sphere (one could be loosely bound and lost in the mass spectrometry ionization process), these data are in agreement. 
     A molecules dipole moment (D, Debye) and molecular volume (V, A 3 ) are two important factors when determining a medicinal agents solubility in different solvents, particularly water. These two parameters form a DN ratio that is important to fully understand or predict solubility. While dipole moment is an important factor for solubility, the volume over which the charge needs to be considered. 
     Table 12 provides the dipole moment (D), molecular volume (V), and the DN ratio for a number of common solvents for comparison and reference in this study. Calculated variables extend from the non-polar solvent hexane (DN of 0.0) to the polar solvent water (D/V of 0.090) (Table 12). Previous studies developed a parameter called the Aqueous Stability Factor (ASF) to indicate an individual complex&#39;s solubility and stability in an aqueous environment. This parameter combines the calculated complex energy (C), average Cu—O+Cu—N bond length (L), dipole moment (D), and molecular charge (Z): 
         ASF =( E*L )/( D*Z )  (8)
 
     The complex stability is approximated by the complex energy, because the smaller or more negative the complex energy, the more stable it should be. Bond distance is a function of covalency, so the Average Bond Length helps us determine how strong the bond is with the chelated atom. Dipole Moment helps us determine solubility to a degree, so a larger Dipole value should signify greater solubility. The Molecular Charge is included because increasing charges also improve molecular solubility. The initial Aqueous Stability Factor value is expressed as units of J*m/D. Molecular Volume has been added to better correlate the ASF with a complex&#39;s solubility in solution. The modified version is given as: 
         ASF =( E*L )/(( D/V )* Z )  (9)
 
     Which can be rearranged to: 
         ASF =( E*L*V )/( D*Z )  (10)
 
     The improved ASF is used in this study an expressed as units J*m 4 /D. 
     In Tables 13 and 14, column 1 refers the bonding configuration of the central Cu atom to the respective oxygen atoms. Since one nitrogen atom is located in the taxol structure number labeling is not required. In all complexes, the single Nitrogen occupies the first binding site. In Table 13, there are five numbers under the Configuration column referring to the five Cu—O bonds that occupy binding sites 2-6. In Table 14 there are four numbers referring to the four Cu—O bonds occupying binding sites 2-5, with the sixth binding site being occupied by H 2 O. In all complexes Cu is chelated as a central hexavalent atom with an octahedral geometry. 
     Column 2 lists the Method under which each complex was calculated, where NS=Neutral Singlet, CS=Cation Singlet, and CD=Cation Doublet. Column 3 lists the bond distances used to calculate the Average Bond Length. In Table 13, the values listed 2 nd  to 6 th  are in the same order as, and correspond to the configuration provided in Column 1, with the single Cu—N bond listed first. In Table 14, the values listed 2 nd  to 5 th  are in the same order as, and correspond to the configuration provided in Column 1, with the first number being the Cu—N bond, and the last the Cu—H 2 O. In both charts, Bond Average, Volume, Dipole, Energy, and Charge are the values used to calculate the ASF value present in Column 11. Also provided in the chart are D/V values in Column 8 and Molecular Area in Column 5. Table 15 provides the average values for each group of complexes, uncomplexed taxol, copper-taxol complex, and the copper-taxol-water complex. 
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 Total possible number of copper(II)-taxol combinations 
               
               
                 based on the permutations equation n!/((r!(n − r)!). 
               
               
                 Possible combinations n!/((r!(n − r)!) 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Group 
                 N 
                 R 
                 Total 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 Cu-Taxol 
                 14 
                 5 
                 2002 
               
               
                   
                 Cu-Taxol-H 2 O 
                 14 
                 4 
                 1001 
               
               
                   
                 Copper(II)-taxol refined 
                 9 
                 5 
                 126 
               
               
                   
                 Cu-Taxol-H 2 O refined 
                 9 
                 4 
                 126 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 A list of common solvents with their calculated dipole moment (D), 
               
               
                 molecular volume (Å 3 ), and D/V ratio (Debye/Å 3 ). 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Dipole 
                 Molecular 
                 D/V 
               
               
                   
                 Name 
                 Moment (D) 
                 Volume (Å 3 ) 
                 (Debye/Å 3 ) 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 Water 
                 1.74 
                 19.24 
                 0.09 
               
               
                   
                 Methanol 
                 1.54 
                 40.66 
                 0.038 
               
               
                   
                 Ethanol 
                 0.148 
                 59.08 
                 0.025 
               
               
                   
                 1-Propanol 
                 0.159 
                 77.37 
                 0.02 
               
               
                   
                 1-Butanol 
                 1.6 
                 95.69 
                 0.017 
               
               
                   
                 1-3 Butanediol 
                 3.23 
                 102.19 
                 0.031 
               
               
                   
                 1-Pentanol 
                 1.41 
                 114.06 
                 0.012 
               
               
                   
                 1-Octanol 
                 1.62 
                 168.95 
                 0.0096 
               
               
                   
                 Hexane 
                 0 
                 124.8 
                 0 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 A summary of taxol and copper(II)-taxol complex computational results (note E represents exponent or to the power of ten). 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 Dipole 
                   
                   
                   
                   
               
               
                   
                   
                 Cu—N, Cu—O 
                 Bond 
                   
                 Volume 
                 Moment 
               
               
                   
                   
                 Bond 
                 Average 
                   
                 (V, 
                 (D, 
                   
                 Energy 
                   
                 ASF 
               
               
                 Configuration 
                 Method 
                 Distances (Å) 
                 (Å) 
                 Area (Å 2 ) 
                 Å 3 ) 
                 Debye) 
                 D/V 
                 (kJ/mol) 
                 Charge 
                 (J * m 4 /D) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Taxol 
                 CD 
                 NA 
                 1 
                 793.73 
                 827.88 
                 5.41 
                 0.00653 
                 1316.7005 
                 1 
                 2.01492E−32 
               
               
                 Taxol 
                 NS 
                 NA 
                 1 
                 784.63 
                 826.94 
                 5.03 
                 0.00608 
                 1316.7005 
                 0 
                 2.16468E−32 
               
               
                 {1, 2, 3, 7, 8} 
                 CS 
                 1.901, 1.845, 
                 1.85466 
                 778.82 
                 830.84 
                 1.95 
                 0.00234 
                 1438.7161 
                 1 
                  1.1369E−31 
               
               
                   
                   
                 1.862, 1.431, 
               
               
                   
                   
                 2.182, 1.907 
               
               
                 {1, 2, 3, 7, 13} 
                 CS 
                 1.830, 1.856, 
                 1.859 
                 769.18 
                 829.14 
                 20.37 
                 0.02456 
                 1245.8209 
                 1 
                 9.42696E−33 
               
               
                   
                   
                 1.860, 1.871, 
               
               
                   
                   
                 1.874, 1.863 
               
               
                 {1, 2, 7, 8, 13} 
                 CS 
                 1.911, 1.861, 
                 1.8851 
                 769.39 
                 836.36 
                 15.59 
                 0.01864 
                 1579.0774 
                 1 
                 1.59698E−32 
               
               
                   
                   
                 1.865, 1.941, 
               
               
                   
                   
                 1.877, 1.856 
               
               
                 {2, 3, 7, 8, 13} 
                 CS 
                 1.924, 1.853, 
                 1.997 
                 752.61 
                 825.43 
                 10.43 
                 0.01263 
                 2470.5863 
                 1 
                 3.90458E−32 
               
               
                   
                   
                 2.307, 2.110, 
               
               
                   
                   
                 1.917, 1.871 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                 Cu-Taxol-H 2 O Complex Computational Results. The first bond distance value is the Cu—N bond, the subsequent 4 bonds listed 
               
               
                 are the Cu—O bonds, and final bond value is the Cu—H 2 O bond (note E represents exponent or to the power of ten). 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                 Bond 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                 Distance (Å) 
                 Bond 
               
               
                   
                   
                 Cu—N/Cu—O/ 
                 Average 
                 Area 
                 Volume 
                 Dipole 
                 D/V 
                 Energy 
                   
                 ASF 
               
               
                 Configuration 
                 Method 
                 Cu—H 2 O 
                 (Å) 
                 (Å 2 ) 
                 (Å 3 ) 
                 (D) 
                 (Å) 
                 (kJ/mol) 
                 Charge 
                 (J * m 4 /D) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 {1, 2, 3, 5} 
                 CD 
                 1.879, 1.860, 
                 1.868 
                 794.64 
                 849.06 
                 6.83 
                 0.0080 
                 1270.5832 
                 1 
                 2.95104E−32 
               
               
                   
                   
                 1.855, 1.854, 
               
               
                   
                   
                 1.869, 1.893 
               
               
                 {1, 2, 3, 7} 
                 CD 
                 1.865, 1.861, 
                 1.862 
                 789.31 
                 846.57 
                 18.7 
                 0.02208 
                 876.4494 
                 1 
                   7.39E−33 
               
               
                   
                   
                 1.850, 1.852, 
               
               
                   
                   
                 1.863, 1.884 
               
               
                 {1, 2, 3, 8} 
                 CD 
                 1.879, 1.855, 
                 1.872 
                 787.22 
                 848.57 
                 7.51 
                 0.00885 
                 1248.9703 
                 1 
                 2.64184E−32 
               
               
                   
                   
                 1.862, 1.852, 
               
               
                   
                   
                 1.895, 1.889 
               
               
                 {1, 2, 3, 13} 
                 CD 
                 1.896, 1.852, 
                 1.872 
                 791.44 
                 848.73 
                 5.91 
                 0.00696 
                 1920.5067 
                 1 
                 5.16348E−32 
               
               
                   
                   
                 1.843, 1.862, 
               
               
                   
                   
                 1.888, 1.892 
               
               
                 {1, 2, 5, 13} 
                 CD 
                 1.887, 1.927, 
                 1.949 
                 766.59 
                 840.64 
                 13.16 
                 0.01565 
                 1228.5981 
                 1 
                 1.53025E−32 
               
               
                   
                   
                 2.249, 1.863, 
               
               
                   
                   
                 1.868, 1.905 
               
               
                 {1, 2, 7, 8} 
                 CD 
                 1.890, 1.872, 
                 1.868 
                 794.65 
                 846.34 
                 17.43 
                 0.0205 
                 2889.4995 
                 1 
                 2.62205E−32 
               
               
                   
                   
                 1.845, 1.855, 
               
               
                   
                   
                 1.858, 1.893 
               
               
                 {1, 2, 7, 13} 
                 CD 
                 1.846, 1.864, 
                 1.892 
                 786.91 
                 845.66 
                 14 
                 0.01655 
                 3196.9308 
                 1 
                 3.65361E−32 
               
               
                   
                   
                 1.855, 1.956, 
               
               
                   
                   
                 1.880, 1.951 
               
               
                 {1, 3, 5, 13} 
                 CD 
                 1.904, 1.846, 
                 1.889 
                 774.14 
                 846.12 
                 9.17 
                 0.01083 
                 1389.983 
                 1 
                 2.42358E−32 
               
               
                   
                   
                 1.946, 1.854, 
               
               
                   
                   
                 1.892, 1.896 
               
               
                 {1, 3, 7, 8} 
                 CD 
                 1.903, 1.861, 
                 1.877 
                 789.45 
                 848.89 
                 14.63 
                 0.01723 
                 3053.5593 
                 1 
                 3.32566E−32 
               
               
                   
                   
                 1.860, 1.864, 
               
               
                   
                   
                 1.863, 1.911 
               
               
                 {1, 3, 7, 13} 
                 CD 
                 1.891, 1.856, 
                 1.870 
                 783.97 
                 846.87 
                 12.38 
                 0.01461 
                 1526.7282 
                 1 
                 1.95316E−32 
               
               
                   
                   
                 1.849, 1.865, 
               
               
                   
                   
                 1.873, 1.887 
               
               
                 {1, 7, 8, 13} 
                 CD 
                 1.891, 1.857, 
                 1.878 
                 788.43 
                 850.47 
                 16.85 
                 0.01981 
                 1398.5588 
                 1 
                 1.32591E−32 
               
               
                   
                   
                 1.877, 1.866, 
               
               
                   
                   
                 1.881, 1.898 
               
               
                 {1, 9, 11, 13} 
                 CD 
                 1.940, 1.845, 
                 1.888 
                 760.72 
                 840.01 
                 9.22 
                 0.0109 
                 2447.6548 
                 1 
                 4.21209E−32 
               
               
                   
                   
                 1.872, 1.874, 
               
               
                   
                   
                 1.898, 1.904 
               
               
                 {2, 3, 7, 8} 
                 CD 
                 1.907, 1.914, 
                 1.938 
                 787.24 
                 843.15 
                 13.09 
                 0.01552 
                 1886.933 
                 1 
                 2.35566E−32 
               
               
                   
                   
                 1.827, 1.929, 
               
               
                   
                   
                 2.165, 1.887 
               
               
                 {2, 3, 7, 13} 
                 CD 
                 1.963, 1.858, 
                 1.901 
                 790.08 
                 844.45 
                 4.44 
                 0.0052 
                 1974.5689 
                 1 
                 7.13976E−32 
               
               
                   
                   
                 1.864, 1.946, 
               
               
                   
                   
                 1.873, 1.903 
               
               
                 {2, 7, 8, 13} 
                 CD 
                 1.877, 1.847, 
                 1.939 
                 784.87 
                 844.96 
                 16.24 
                 0.01921 
                 2226.6473 
                 1 
                 2.24713E−32 
               
               
                   
                   
                 1.843, 2.058, 
               
               
                   
                   
                 2.104, 1.909 
               
               
                 {3, 7, 8, 13} 
                 CD 
                 1.909, 1.865, 
                 1.964 
                 750.26 
                 845.03 
                 11.51 
                 0.01362 
                 2493.3358 
                 1 
                 3.59547E−32 
               
               
                   
                   
                 1.911, 2.251, 
               
               
                   
                   
                 1.879, 1.970 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 15 
               
             
            
               
                   
               
               
                 Average Values of complexes grouped by type for comparison (note E represents exponent or to the power of ten). 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 Bond 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 Average 
                   
                 Volume 
                 Dipole 
                   
                 Energy 
                   
                 ASF 
               
               
                   
                 (Å) 
                 Area (Å 2 ) 
                 (Å 3 ) 
                 (Debye) 
                 D/V 
                 (kJ/mol) 
                 Charge 
                 (J * m 4 /D) 
                 V/A (Å) 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Taxol 
                 N/A 
                 789.18 
                 827.41 
                 5.22 
                 0.00630 
                 1316.7005 
                 0 
                 — 
                 1.04847 
               
               
                 Cu-Taxol 
                 1.898958 
                 767.5 
                 830.4425 
                 12.085 
                 0.01454 
                 1683.55 
                 1 
                 4.45332E−32 
                 1.08213 
               
               
                 Cu-Taxol- 
                 1.895802 
                 782.495 
                 845.97 
                 11.9418 
                 0.01411 
                 1939.34 
                 1 
                 2.99248E−32 
                 1.08136 
               
               
                 H 2 O 
               
               
                   
               
            
           
         
       
     
     Comparing the values present in table 14 and 15, it can be observed that there is only a negligible difference in the average bond distances between both the copper(II)-taxol and the copper(II)-taxol-H 2 O complexes. The average volume of the copper(II)-taxol complexes is very similar to that of the uncomplexed taxol molecule. The average volume of the copper(II)-taxol complexes is 830.442 Å 3  and the volume of uncomplexed taxol is 827.41 Å 3 , showing an average difference of 0.367%. The average difference is monohydrated complexes is 2.24%. The dipole moment values rose drastically for the copper(II)-taxol (0.0141D) and copper(II)-taxol-H 2 O (0.0141D) complexes verses uncomplexed taxol molecule (0.0063D), demonstrating that that solubility is improved in an aqueous environment for the copper(II)-taxol complexes. Taxol is often measured as a sodium adduct in mass spectrometry studies but in water this is a strong electrolyte (Na-taxol Na + +taxol) so the +1 charge associated with the sodium ion does not apply and the ASF for uncomplexed can not be calculated. 
     The D/V ratios also rose significantly for each group of complexes as well in relation to basic taxol. The average energy of both groups of complexes also rose in relation to the uncomplexed taxol. These computational exercises demonstrate that the copper (II)-taxol complex has a significantly higher water solubility, important for the physiological environment. 
     The binding of copper (II) to quinine and taxol is demonstrated. The World Health Organization of essential medicines includes many pharmaceutical agents that contain amines and have low water solubility. We have also used computational methods to show the water solubility of many of these species can be improved by binding the copper (II) ion. The copper (II) ion presents an economical method to increase the medical efficiency of hundreds of pharmaceutical agents currently on the market.