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Definitions

• STATs are activated at a very early stage involving protein tyrosine kinase phosphorylation of tyrosine of growth factor receptors, receptor- associated Janus kinase (Jaks) or Src kinase families. This in turn induces phosphotyrosine (pTyr)-SH2 interactions between two STAT monomers in the formation of dimers, translocation to the nucleus, and binding to specific DNA response elements regulating gene expression essential for cell proliferation, differentiation, development and survival.
• Normal STAT activation is tightly-regulated and has a short duration, which is in keeping with normal cellular requirements for mounting a response to external stimuli.
• STAT proteins particularly Stat3 and Stat5
• STAT proteins include those breast, prostate and head and neck squamous carcinoma cells, lymphomas and leukemias
• cisplatin induces activation of members of the mitogen-activated protein kinase (MAPK) pathways (Persons et al, 1999; Sanchez-Perez et al, 1998), which may influence drug-induced apoptosis.
• MAPK mitogen-activated protein kinase
• the subject invention concerns platinum complexes and uses thereof.
• the platinum complexes of the invention can be used to treat oncological, viral, bacterial, and parasitic disease conditions.
• Figure 1 shows the results in graph form from an MTT assay. Cisplatin is also designated as “Cis-Pt.”
• Figure 2 shows the results in graph form from an MTT assay. Cisplatin is also designated as “Cis-Pt.”
• Figure 3 shows the results in graph form from an XTT assay. Cisplatin is also designated as “Cis-Pt.”
• Figure 4 shows the results in graph form from an MTT assay. Cisplatin is also designated as "Cis-Pt.”
• Figures 5A-C show inertness of CPA-7 platinum complex to reduction by glutathione. 20 ⁇ m CPA-7 in PBS/20% DMSO with 10 mm glutathione. As shown in Figure
• FIG. 9 shows the results in graph form from an MTT assay.
• the figure legend identifies the Pt(NO 2 )(NH 3 ) 2 (Cl) 2 A platinum complex by the "A" substituent identified herein. Cisplatin is also designated as "Cis-Pt.”
• Two different isolates of the platinum (TV) complex substituted with Safranin were isolated (referred to herein as Safranin 1 and Safranin
• FIG. 10 shows the results in graph form from an XTT assay.
• the figure legend identifies the Pt(NO 2 )(NH 3 ) 2 (Cl) 2 A platinum complex by the "A” substituent identified herein.
• Figure 11 shows the results in graph form from an MTT assay.
• the figure legend identifies the Pt(NO 2 )(NH 3 ) 2 (Cl) 2 A platinum complex by the "A” substituent identified herein.
• Cisplatin is also designated as "Cis-Pt.”
• Figures 12A-B are photographs showing nuclear extracts containing activated Statl and Stat3 are treated with the indicated concentrations of other platinum (IN) complexes
• HK 104 (designated herein as HK 104, HK 105, HK 106, HK 107, HK 108, HK 109, HK 110, HK
• SEQ ID ⁇ O:l is the nucleotide sequence of an oligonucleotide probe.
• Platinum complexes of the invention can induce apoptosis and/or inhibit tumor cell growth and can also be used to treat cancers.
• the platinum complexes of the invention also can be used as antiviral, antibacterial, and antiparasitic agents. It has been suggested that cellular cytotoxicity of platinum (IN) compounds is a result of platinum (IV) compounds being reduced to platinum (II) in the cell. Surprisingly, platinum (IN) complexes of the present invention may not require this type of reduction in the cells to have a cytotoxic effect.
• platinum complexes of the present invention are distinct from platinum compounds in the art by maintaining their correct oxidative conformation as platinum (IN) compounds which are more effective than the existing platinum (II) compounds, hi addition, platinum complexes of the invention can also form nitric oxide in the cells as radicals thereby killing the cells through the formation of oxide radicals.
• Platinum complexes of the invention include those complexes having the structure shown in formula I:
• X and Y are, inde endently, any halogen, - ⁇ O 2 , -ONO, or the structure:
• R 1 is -NO 2 or -ONO
• R 2 is any halogen, -OH, -ONO, -ONO 2 , -COR 10 , -OPO 3 R 10 R n , -OSO 3 H, -OSeOOH, - SeOOH, -AsO 2 , -OAsO 2 , -NR 10 R ⁇ , -NHR 10 R n , -OOCR 15 , alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, alkycarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, heteroalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocycloalkoxy, or heterocycloalkoxycarbonyl, any of which can be optionally substituted with any halogen, -COOH,
• R 3 is, independently, -NH 3 , or -NHR 7 ;
• R 7 is H, C ⁇ - 6 alkyl, alkoxy, or aryl, optionally substituted with -NO 2 or -COOH;
• R 10 and R ⁇ are, independently, H, -NH 2 , -OH, -NHR 7 , CONHR 7 , CON(R 7 ) 2 , d- 6 alkyl, aryl, or heteroaryl, any of which can be optionally substituted with any halogen, -COOH, -OH, -
• R 15 is alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, alkycarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, heteroalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocycloalkoxy, or heterocycloalkoxycarbonyl, any of which can be optionally substituted with any halogen, -COOH, -OH, -NO 2 , -NH 2 , -N-alkyl, alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, alkycarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, heteroalkyl, heterocycloalkylcarbonyl, heteroaryl,
• X and Y can be, independently, fluorine (F), chlorine (CI), bromine (Br) or iodine (I).
• X is CI and Y is CI.
• R is -NO 2
• R is CI and R is -NH 3 .
• Platinum complexes of the invention can also have the structure shown in formula II:
• X and Y are, independently, any halogen, or the structure:
• R 4 is -NO 2 or -ONO
• R 5 is any halogen, -OH, -ONO, -ONO 2 , -COR 10 , -OPO 3 R 10 R ⁇ , -OSO 3 H, -OSeOOH, - SeOOH,
• -AsO 2 , -OAsO 2 , -NR 10 R n , -NHR 10 R n , -OOCR 15 alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, alkycarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, heteroalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocycloalkoxy, or heterocycloalkoxycarbonyl, any of which can be optionally substituted with any halogen, -COOH, -OH, -NO 2 , -NH 2 , -N- alkyl, alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, alkycarbonyl, alkoxycarbony
• R 6 is, independently, NH 2 or NH; 7
• R is H, C ⁇ - 6 alkyl, alkoxy, aryl, optionally substituted with -NO 2 or -COOH;
• R 8 and R 9 are, independently, H, C ⁇ - 6 alkyl, or -OH, any of which can be optionally substituted with any halogen, -COOH, -OH, -NO 2 , -NH , alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, alkycarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, heteroalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocycloalkoxy, or heterocycloalkoxycarbonyl;
• R 10 and R 11 are, independently, H, -NH 2 , -OH, -NHR 7 , CONHR 7 , CON(R 7 ) 2 , C ⁇ - 6 alkyl, aryl, or heteroaryl, any of which can be optional
• R and R are, independently, H or C ⁇ . . 6 alkyl, or R and R together form an aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, any of which can be optionally substituted with any halogen, -COOH, -OH, -NO 2 , -NH 2 , alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, alkycarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, heteroalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocycloalkoxy, or heterocycloalkoxycarbonyl;
• R 15 is alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, alkycarbony
• X and Y can be, independently, fluorine (F), chlorine (CI), bromine (Br) or iodine (I).
• X is CI and Y is CI.
• R 4 is -NO 2
• R 5 is CI
• R 6 is -NH 2
• n is 0.
• Platinum complexes of the invention can also have the structure shown in formula III or TV:
• X and Y are, independently, any halogen, - ⁇ O 2 , -ONO, or X and Y together form the structure:
• R 6 is, independently, NO , N, NH, or NH 2 ;
• R 8 and R 9 are, mdependently, H, C ⁇ - 6 alkyl, or -OH, any of which can be optionally substituted with any halogen, -COOH, -OH, -NO 2 , -NH 2 , alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, alkycarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, heteroalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroa ⁇ l- ⁇ yc'a 0rb /onyl, heterocycloalkoxy, or heterocycloalkoxycarbonyl;
• R 12 and R 13 are, mdependently, H or C ⁇ - 6 alkyl, or R 12 and R 13 together form an aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, any of which can be optionally substituted with any halogen, -COOH, -OH, -NO 2 , -NH , alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, alkycarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, heteroalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocycloalkoxy, or heterocycloalkoxycarbonyl; n is any integer from 0 to 6; or a pharmaceutically acceptable salt thereof.
• X and Y can be, independently, fluorine (F), chlorine (CI), bromine (Br) or iodine (I).
• X is CI and Y is CI.
• platinum complexes that are not defined by formula I or formula II but that are specifically exemplified in the Table 5 presented herein. Exemplified embodiments of platinum complexes of the invention are shown in Table 5. The chemical structure of a complex along with a designation name (e.g.,
• X and Y are, independently, any halogen, -OH, H 2 O, or -SO(CH 3 ) 2 ; and A can be any of the following: (safranin)
• R 1 is, independently, NH 2 or NH;
• R 2 and R 3 are, independently, H, -OH, C ⁇ - 6 alkyl, alkoxy, cycloalkyl, aryloxy, cycloalkoxy, aryl, heteroalkyl, heterocycloalkyl, heteroaryl, arylcarbonyl, and heteroarylcarbonyl, any of which can be optionally substituted with alkyl, alkoxy, cycloalkyl, aryloxy, cycloalkoxy, aryl, heteroalkyl, heterocycloalkyl, heteroaryl, arylcarbonyl, and heteroarylcarbonyl.
• R 4 and R 5 are, independently, H or C ⁇ - 6 alkyl, alkoxy, cycloalkyl, aryloxy, cycloalkoxy, aryl, heteroalkyl, heterocycloallcyl, heteroaryl, arylcarbonyl, and heteroarylcarbonyl or R 4 and R 5 together form a cycloalkyl, cycloalkoxy, aryl, aryloxy, heterocycloalkyl, heteroaryl, arylcarbonyl, and heteroarylcarbonyl, any of which can be optionally substituted with alkyl, alkoxy, cycloalkyl, aryloxy, cycloalkoxy, aryl, heteroalkyl, heterocycloalkyl, heteroaryl, arylcarbonyl, and heteroarylcarbonyl; n is any integer from 0 to 6; or a pharmaceutically acceptable salt thereof.
• X and Y can be, independently, chlorine (CI), bromine (Br) or iodine (I).
• X is CI and Y is CI.
• alkyl means straight or branched chain, saturated or mono- or polyunsaturated hydrocarbon groups having from 1 to 20 carbon atoms and - alkyl means straight or branched chain alkyl groups containing from one up to X carbon atoms.
• C ⁇ . 6 alkyl means straight or branched chain alkyl groups containing from one up to 6 carbon atoms.
• Alkoxy means an alkyl-O-group in which the alkyl group is as previously described.
• Cycloalkyl includes a nonaromatic monocyclic or multicychc ring system, including fused and spiro rings, of from about three to about 10 carbon atoms.
• a cyclic alkyl may optionally be partially unsaturated.
• Cycloalkoxy means a cycloalkyl-O-group in which cycloalkyl is as defined herein.
• Aryl means an aromatic monocyclic or multicychc carbocyclic ring system, including fused and spiro rings, containing from about six to about 14 carbon atoms.
• Aryloxy means an aryl-O-group in which the aryl group is as described herein.
• Alkylcarbonyl means a RC(O)- group where R is an alkyl group as previously described.
• Alkoxycarbonyl means an ROC(O)- group where R is an alkyl group as previously described.
• Cycloalkylcarbonyl means an RC(O)- group where R is a cycloalkyl group as previously described.
• Cycloalkoxycarbonyl means an ROC(O)- group where R is a cycloalkyl group as previously described.
• Heteroalkyl means a straight or branched-chain having from one to 20 carbon atoms and one or more heteroatoms selected from nitrogen, oxygen, or sulphur, wherein the nitrogen and sulphur atoms may optionally be oxidized, i.e., in the form of an N-oxide or an S-oxide.
• Heterocycloalkyl means a monocyclic or multicychc ring system (which may be saturated or partially unsaturated), including fused and spiro rings, of about five to about 10 elements wherein one or more of the elements in the ring system is an element other than carbon and is selected from nitrogen, oxygen, silicon, or sulphur atoms.
• Heteroaryl means a five to about a 14-membered aromatic monocyclic or multicychc hydrocarbon ring system, including fused and spiro rings, in which one or more of the elements in the ring system is an element other than carbon and is selected from nitrogen, oxygen, silicon, or sulphur and wherein an N atom may be in the form of an N-oxide.
• Arylcarbonyl means an aryl-CO-group in which the aryl group is as described herein.
• Heteroarylcarbonyl means a heteroaryl-CO- group in which the heteroaryl group is as described herein and heterocycloalkylcarbonyl means a heterocycloalkyl-CO-group in which the heterocycloalkyl group is as described herein.
• Aryloxycarbonyl means an ROC(O)- group where R is an aryl group as previously described.
• Heteroaryloxycarbonyl means an ROC(O)- group where R is a heteroaryl group as previously described.
• Heterocycloalkoxy means a heterocycloalkyl-O- group in which the heterocycloalkyl group is as previously described.
• Heterocycloalkoxycarbonyl means an ROC(O)- group where R is a heterocycloalkyl group as previously described.
• saturated alkyl groups include, but are not limited to, methyl, ethyl, N- propyl, isopropyl, N-butyl, tert-butyl, isobutyl, sec-butyl, N-pentyl, N-hexyl, N-heptyl, and N-octyl.
• An unsaturated alkyl group is one having one or more double or triple bonds.
• Unsaturated alkyl groups include, for example, ethenyl, propenyl, butenyl, hexenyl, vinyl, 2- propynyl, 2-isopentenyl, 2-butadienyl, ethynyl, 1-propynyl, 3-propynyl, and 3-butynyl.
• Cycloalkyl groups include, for example, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3- cyclohexenyl, and cycloheptyl.
• Heterocycloalkyl groups include, for example, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 3 -morpholmyl, 4-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and 1,4-diazabicyclooctane.
• Aryl groups include, for example, phenyl, indenyl, biphenyl, 1- naphthyl, 2-naphthyl, anthracenyl, and phenanthracenyl.
• Heteroaryl groups include, for example, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridyl, indolyl, quinolinyl, isoquinolinyl, benzoquinolinyl, carbazolyl, and diazaphenanthrenyl.
• halogen means the elements fluorine (F), chlorine (CI), Bromine (Br), and iodine (I).
• pharmaceutically-acceptable salts means salts of the platinum complexes of the invention which are prepared with acids or bases, depending on the particular substituents present on the subject complexes described herein.
• a pharmaceutically- acceptable base addition salts include sodium, potassium, calcium, ammonium, or magnesium salt.
• pharmaceutically-acceptable acid addition salts include hydrochloric, hydrobromic, nitric, phosphoric, carbonic, sulphuric, and organic acids like acetic, propionic, benzoic, succinic, fumaric, mandelic, oxalic, citric, tartaric, maleic, and the like.
• Pharmaceutically-acceptable salts of platinum complexes of the invention can be prepared using conventional techniques.
• platinum complexes of the invention may contain one or more asymmetrically substituted carbon atoms which can give rise to stereoisomers. All such stereoisomers, including enantiomers, and diastereoisomers and mixtures, including racemic mixtures thereof, are contemplated within the scope of the present invention. Platinum complexes of the present invention are potent and selective disruptors of STAT activity.
• the complexes designated herein as CPA-7, CPA-10, CPA-39 (HK104), CPA-43 (HK106), CPA-46 (HK111), CPA-51 (HK110), CPA-55 (HK109), CPA-30 (HK112), and CPA-41 strongly disrupt Stat3 activity and interfere with its ability to bind to its consensus binding sequence.
• Platinum complexes of the invention can induce cell growth inhibition and apoptosis in transformed and tumor cells with persistently active STATs. Malignant cells with aberrant or constitutive STAT signaling are highly sensitive to platinum complexes of the invention. General cytotoxicity of the subject platinum complexes to normal cells is minimal or nil.
• Methods of the invention comprise inhibiting function of a STAT by contacting a cell expressing a STAT with a platinum complex of the invention wherein the complex is taken in or otherwise provided inside the cell.
• Platinum complexes of the invention can physically interact with the DNA-binding domain of Stat3 and thereby disrupts its ability to bind to DNA.
• CPA-1 and CPA-7 abrogate Stat3 signaling function and thereby induce cell growth inhibition and apoptosis.
• Methods of the invention also comprise inhibiting the function and/or growth and replication of a cell that is aberrantly or constitutively expressing a STAT, such as Statl or Stat3.
• the method comprises contacting a cell with a platinum complex of the invention.
• the cell is a tumor cell, cancer cell, or a transformed cell.
• the cell can be a cell from a mammal, including human, monkey, chimpanzee, ape, dog, cat, cow, pig, and horse.
• Platinum complexes of the invention can be delivered to a cell either through direct contact with the cell or via a carrier means.
• Carrier means for delivering compositions to cells are known in the art and include, for example, encapsulating the composition in a liposome moiety.
• Another means for delivery of platinum complexes of the invention to a cell comprises attaching the platinum complexes to a protein or nucleic acid that is targeted for delivery to the target cell.
• 20030032594 and 20020120100 disclose amino acid sequences that can be coupled to another composition and that allows the composition to be translocated across biological membranes.
• Published U.S. Patent Application No. 20020035243 also describes compositions for transporting biological moieties across cell membranes for intracellular delivery.
• the subject invention also concerns methods for treating oncological or inflammatory disorders in a patient.
• an effective amount of a platinum complex of the present invention is administered to a patient having an oncological or inflammatory disorder and who is in need of treatment thereof.
• Methods of the invention can optionally include identifying a patient who is or may be in need of treatment of an oncological or inflammatory disorder.
• the patient can be a human or other mammal, such as a primate (monkey, chimpanzee, ape, etc.), dog, cat, cow, pig, or horse, or other animals having an oncological disorder.
• a primate monkey, chimpanzee, ape, etc.
• Means for administering and formulating platinum complexes for administration to a patient are known in the art, examples of which are described herein.
• Oncological disorders include cancer and/or tumors of the bone, breast, kidney, mouth, larynx, esophagus, stomach, testis, cervix, head, neck, colon, ovary, lung, bladder, skin, liver, muscle, pancreas, prostate, blood cells (including lymphocytes), and brain.
• Inflammatory disorders include arthritis, multiple sclerosis, lupus, Crohn's disease, and related neurological and inflammatory connective tissue diseases (e.g., Sj ⁇ gren's syndrome).
• the platinum complexes of this invention can be administered to a patient in need of treatment in combination with other antitumor or anticancer substances or with radiation therapy or with surgical treatment to remove a tumor. These other substances or radiation treatments may be given at the same as or at different times from the platinum complexes of this invention.
• the platinum complexes of the present invention can be used in combination with mitotic inhibitors such as taxol or vinblastine, alkylating agents such as cyclophosamide or ifosfamide, antimetabolites such as 5-fluorouracil or hydroxyurea, DNA intercalators such as adriamycin or bleomycin, topoisomerase inhibitors such as etoposide or camptothecin, antiangiogenic agents such as angiostatin, antiestrogens such as tamoxifen, and/or other anti-cancer drugs or antibodies, such as, for example, GLEEVEC (Novartis Pharmaceuticals Corporation) and HERCEPTIN (Genentech, Inc.), respectively.
• mitotic inhibitors such as taxol or vinblastine
• alkylating agents such as cyclophosamide or ifosfamide
• antimetabolites such as 5-fluorouracil or hydroxyurea
• DNA intercalators such as adriamycin or bleomycin
• Epstein-Barr Virus is associated with a number of mammalian malignancies.
• the platinum complexes of the subject invention can be used alone or in combination with anticancer or antiviral agents, such as ganciclovir, azidothymidine (AZT), lamivudine (3TC), etc., to treat patients infected with a virus that can cause cellular transformation and/or to treat patients having a tumor or cancer that is associated with the presence of viral genome in the cells.
• the platinum complexes of the subject invention can also be used in combination with viral based treatments of oncologic disease.
• platinum complexes of the invention can be used with mutant herpes simplex virus in the treatment of non-small cell lung cancer (Toyoizumi et al. , 1999).
• the subject invention also concerns methods for treating bacterial and viral infections of a patient using a platinum complex of the invention.
• an effective amount of a platinum complex of the invention is administered to a patient having a bacterial or viral infection.
• Methods of the invention can optionally include identifying a patient who is or may be in need of treatment of a bacterial or viral infection.
• the patient can be a human or other mammal, such as a primate (monkey, chimpanzee, ape, etc.), dog,, cat, cow, pig, or horse, or other animal infected with a bacteria or virus.
• Bacterial infections that can be treated according to the present invention include those from Staphylococcus, Streptococcus, Salmonella, Bacillus, Clostridium, Pseudomonas, Neisseria, Mycobacterium, and Yersinia.
• Viral infections that can be treated according to the present invention include, but are not limited to, those associated with human immunodeficiency virus (HIV), human T cell leukemia virus (HTLV), Papillomavirus (e.g, human papilloma virus), Polyomavirus (e.g., SV40, BK virus, DAR virus), orthopoxvirus (e.g., variola major virus (smallpox virus)), EBV, herpes simplex virus (HSV), hepatitis virus, Rhabdovirus (e.g., Ebola virus) and cytomegalovirus (CMV).
• HCV human immunodeficiency virus
• HTLV human T cell leukemia virus
• Papillomavirus e.g, human papilloma virus
• Polyomavirus e.g., SV40, BK virus, DAR virus
• orthopoxvirus e.g., variola major virus (smallpox virus)
• Platinum compositions of the present invention can also be used to treat viral diseases in the presence of photodynamic therapy (Cuny et al, 1999).
• Platinum complexes of the present invention which can be used in photodynamic therapy include, but are not limited to, the complexes designated herein as CPA-30, CPA-32, CPA-38, CPA-39, CPA-41, CPA-42, CPA-43, CPA-45, CPA-46, CPA-51, CPA-53, CPA-54, CPA-55, and JP5. It is contemplated that these compounds are activated by light to activate their antiviral, antibacterial, antitumor, antiparasitic, or cellular effects.
• Platinum complexes of the subject invention can also be used to treat patients infected with a parasitic organism.
• the patient is administered a therapeutically effective amount of a platinum complex of the present invention.
• Methods of the invention can optionally include identifying a patient who is or may be in need of treatment of a parasitic infection.
• the patient can be a human or other mammal, such as a primate (monkey, chimpanzee, ape, etc.), dog, cat, cow, pig, or horse, or other animal infected with a parasitic organism.
• Disease conditions that can be treated according to the present invention include, but are not limited to, leishmania, toxoplasmosis, schistosomiasis, trypanosomiasis, pneumocystis, malaria, and trichinosis.
• Parasitic organisms that can cause disease conditions treatable according to the present invention include, but are not limited to, Leishmania, Toxoplasma, Schistosoma, Plasmodium, and Trypanosoma.
• the subject invention can also be used to treat gastro-intestinal disorders caused by parasitic organisms such as, Entamoeba, Giardia, Trichomonas, and nematodes such as Ascaris, Trichuris, Enterobius, Necator, Ancylostoma, Strong ides, and Trichinella.
• a platinum complex of the present invention can be administered to patients prophylactically, wherem an uninfected patient is traveling to or will be present in an area where parasitic disease is prevalent or poses a risk to the patient. Accordingly, the patient can be treated with a composition of the present invention prior to the patient's exposure to or presence in the area where parasitic disease is prevalent or poses a risk and/or prior to infection with the parasitic organism.
• Platinum complexes of the present invention can also be used to treat biological products in vitro that are contaminated with or suspected of being contaminated with a virus on a bacterial or parasitic organism.
• Biological products which can be treated with a platinum complexes of the present invention include, but are not limited to, whole blood, fractionated blood, plasma, serum, whole organs, or parts of organs, and cells, including blood cells, muscle cells, skin cells, and neural cells, and products derived from cells.
• Products derived from cells which can be treated with a platinum complex of the present invention include, but are not limited to, interferons, interleukins, blood clotting factors such as factor VIII, IX, X, and the like, insulin, polyclonal and monoclonal antibodies, growth factors, cytokines, and other products.
• Treatment of biological products comprises contacting the product for an effective amount of time and with an effective amount of a platinum complex of the present invention. If necessary, the biological product can be subsequently washed, preferably with a suitable sterile wash solution such as phosphate buffered saline, to remove the platinum complex that was used to treat the product.
• the subject platinum complexes can be administered by any suitable route known in the art including, for example, oral, nasal, rectal, and parenteral routes of administration.
• parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, and intrasternal administration, such as by injection.
• Administration of the subject platinum complexes of the invention can be continuous or at distinct intervals as can be readily determined by a person skilled in the art.
• Platinum complexes of the subject invention can be formulated according to known methods for preparing pharmaceutically useful compositions.
• compositions of the subject invention will be formulated such that an effective amount of the bioactive platinum complex is combined with a suitable carrier in order to facilitate effective administration of the composition.
• suitable carrier in order to facilitate effective administration of the composition.
• the compositions used in the present methods can also be in a variety of forms. These include, for example, solid, semi-solid, and liquid dosage forms, such as tablets, pills, powders, liquid solutions or suspension, suppositories, injectable and infusible solutions, and sprays. The preferred form depends on the intended mode of administration and therapeutic application.
• compositions also preferably include conventional pharmaceutically acceptable carriers and diluents which are known to those skilled in the art.
• carriers or diluents for use with the subject platinum complexes include ethanol, dimethyl sulfoxide, glycerol, alumina, starch, and equivalent carriers and diluents.
• pharmaceutical compositions of the invention will advantageously comprise between about 0.1% and 99%, and especially, 1 and 15% by weight of the total of one or more of the subject platinum complexes based on the weight of the total composition including carrier or diluent.
• the platinum complexes of the subject invention can also be administered utilizing liposome technology, slow release capsules, implantable pumps, and biodegradable containers. These delivery methods can, advantageously, provide a uniform dosage over an extended period of time.
• the platinum complexes of the present invention can also be administered in their salt derivative forms or crystalline forms known to those of ordinary skill in the art.
• the subject invention also concerns a packaged dosage formulation comprising in one or more containers at least one platinum compound of the subject invention formulated in a pharmaceutically acceptable dosage.
• the choice of a sixth ligand includes the availability of a nitrogen, sulfur or oxygen atom in the chemical structure providing a Lewis base for bonding to the oxidized Pt. Other bondings are possible with metals, halides (such as HC1) or through chelation or interaction with pi molecular orbitals.
• One mole of the chosen ligand per mole of cisplatin should be weighed and added to the mixture.
• Organic solvents, such as dichloroethane provide solubility for organic ligands of hydrophobic nature.
• a magnetic stir bar is placed in the mixture and the flask placed on a magnetic stir plate in a chemical fume hood.
• a lecture bottle of dinitrogen tetroxide is fitted with a regulator and Teflon hose, with a glass pipet attached to the hose outlet.
• the pipet tip is inserted into the lower solvent (e.g., dichloroethane) and the lecture bottle warmed slightly with a warm water bath.
• Nitrogen dioxide gas is released at a rate of approximately one bubble per second into the stirring mixture. The gas should be added until all the yellow cisplatin is consumed; the disappearance of yellow solids and yellow solution will indicate consumption of the available cisplatin.
• a blue color is noted to indicate formation of the nitrosyl intermediate; variations in hue and duration of this color have been observed.
• the solvents will evaporate in about two days, leaving a yellow precipitate, which is the product.
• the precipitate can be purified via recrystallization in methanol, DMSO, or other suitable solvent.
• the product can be purified on silica columns or using HPLC.
• MTT Assay 1. Prepare a suspension of A549 cells at 2xl0 5 cells per mL in supplemented DMEM/F12 growth medium. 2. Plate 2xl0 4 cells per well in a 96 well cell culture plate by adding 100 ⁇ L of stock suspension to each well. 3. For each platinum compound (already in solution), prepare a readily usable stock solution in DMEM/F12 medium. 4. For each compound generate triplicate trials of 0, 10, 20, 30, 40, 50, 60, and 70 ⁇ M concentration. This is achieved in situ by adding appropriate volumes of stock solution to each well along with the volume of untreated medium necessary to generate the desired concentration in a final volume of 200 ⁇ L. 5. Gently agitate plates to mix contents.
• XTT Assay A 96-well plate was used for the assays. Approximately 2.5 x 10 4 cells in log phase were added to each well. A platinum complex of the invention was dispensed into each well (dissolved in 20%) DMSO and 80% media), with additional media added as needed to account for uniform volumes. Control wells contained only cells and media. Each concentration assay was performed in triplicate. Plates were incubated for 48 hours at 37 °C with 7.5% CO2. XTT from MD Biosciences, Quebec, was then added according to the provided protocol concentrations and allowed to react for 3 hours. Plates were agitated 5 minutes before reading absorbance at 475 nm on a Varian Gary 50 spectrophotometer with a fibre- optic probe. Percent survival as compared to control wells was plotted against platinum complex concentration.
• Nuclear extract preparation and analysis by EMS A of HK-designated platinum complexes were prepared from NIH3T3/hEGFR cell that overexpress human epidermal growth factor (EGF) receptor and stimulated with EGF (6 ng/ml) for 15 min. Nuclear extracts were pre-incubated with compounds for 30 min at room temperature prior to incubation with radiolabeled probe.
• the 32 P-labeled oligonucleotide probe used is hSIE (high affinity ⁇ -inducible element, m67 variant, 5'-AGCTTCATTTCCCGTAAATCCCTA-3')
• Example 1 MTT assay data for platinum complexes MTT assays are used for the quantitative determination of cellular proliferation and activation and for the quantitation of in vitro tumor cell sensitivity to anti-cancer compounds. The assay is based on the cleavage of the yellow tetrazolium salt MTT into purple colored formazan by metabohcally active cells. Solubilized formazan product can be photometrically quantitated using an ELISA plate reader.
• a decrease in the number of living cells results in a decrease in total metabolic activity which leads to a decrease in color formation.
• Platinum complexes of the present invention were tested in MTT assays using A549 cells to determine anti-cancer cell activity. The results are shown in Tables 1, 2, 3, and 4 and Figures 1, 2 and 4. Table 1 shows percent survival of A549 cells and Table 2 shows the IC50 from the data in Table 1. Figures 1, 2, and 4 show percent survival versus platinum complex concentration in graphical form. Figure 6 shows a graph of absorbance at 570 nm versus concentration of several platinum complexes ( ⁇ m) of the invention.
• Example 2 XTT assay data for platinum complexes
• the XTT assay is based on the conversion of the yellow tetrazalium salt XTT into an orange formazan dye by metabohcally active cells.
• the orange formazan dye is soluble and can be photometrically quantitated using an ELISA plate reader.
• a decrease in the number of living cells results in a decrease in total metabolic activity which leads to a decrease in color formation.
• Platinum complexes of the present invention were tested in XTT assays using A549 cells to determine anti-cancer cell activity. The percent survival of cells versus platinum complex concentration is shown in graphical form in Figures 3 and 7.
• FIGS 5 A-C show the inertness of CPA-7 to glutathione reduction.
• 20 ⁇ m CPA-7 was added in PBS/20% DMSO with 10 mM glutathione.
• the readings were initiated in late evening where data points were collected every 10 minutes at the lambda max for CPA-7, 226 nm.
• the data shows slow reduction which then virtually stops during the night hours, and resumes the next day.
• This data demonstrates sensitivity to light and stability against GSH reduction.
• Data was collected on a Varian Gary 50 fitted with a fibreoptic probe in the kinetics mode.
• the Gary 50 uses a pulsed Xenon lamp with discontinuous irradiation between readings.
• a 25-mL volumetric flask was used for the solution with a magnetic stirring bar at slow speed.
• Example 4 MTT assay data for platinum complexes
• MTT assays are used for the quantitative determination of cellular proliferation and activation and for the quantitation of in vitro tumor cell sensitivity to anti-cancer compounds.
• the assay is based on the cleavage of the yellow tetrazolium salt MTT into purple colored formazan by metabohcally active cells. Solubilized formazan product can be photometrically quantitated using an ELISA plate reader.
• a decrease in the number of living cells results in a decrease in total metabolic activity which leads to a decrease in color formation.
• Platinum complexes of the present invention were tested in MTT assays using A549 cells to determine anti-cancer cell activity. The results are shown in Tables 6, 7, 8, and 9 and Figures 8, 9, and 11.
• Table 6 shows percent survival of A549 cells and Table 7 shows the IC50 from the data in Table 6.
• Figures 8, 9, and 11 show percent survival versus platinum complex concentration in graphical form. * Two different isolates of the platinum (IV) complex substituted with Safranin were isolated (referred to herein as Safranin 1 and Safranin 2) and tested in the assay.
• Example 5 XTT assay data for platinum complexes The XTT assay is based on the conversion of the yellow tetrazalium salt XTT into an orange formazan dye by metabohcally active cells. The orange formazan dye is soluble and can be photometrically quantitated using an ELISA plate reader. A decrease in the number of living cells results in a decrease in total metabolic activity which leads to a decrease in color formation. Platinum complexes of the present invention were tested in XTT assays using A549 cells to determine anti-cancer cell activity. The percent survival of cells versus platinum complex concentration is shown in graphical form in Figure 10.
• Example 6 Inhibition of in vitro Stat3 DNA-binding Activity by HK-designated platinum complexes Other platinum (IN) complexes were evaluated for inliibitory activity against STAT

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