The antineoplastic drug cisplatin (cis-diamminedichloroplatinum or “CDDP”), and related platinum based drugs including carboplatin and oxaliplatin™, are widely used in the treatment of a variety of malignancies, including, but not limited to, cancers of the ovary, lung, colon, bladder, germ cell tumors and head and neck. Platinum analogs are reported to act, in part, by aquation to form reactive aqua species, some of which may predominate intracellularly, and subsequently form DNA intrastrand coordination chelation cross-links with purine bases, thereby cross-linking DNA (predominantly intrastrand crosslinks between purine bases and less commonly as interstrand crosslinks between purine and pyrimidine bases) and disrupting the DNA structure and function, which is cytotoxic to cancer cells. Platinum-resistant cancer cells are resistant to the cytotoxic actions of these agents. Some cancers unpredictably exhibit intrinsic de novo natural resistance to the killing effects of platinum agents and undergo no apoptosis or necrosis or regression following initial platinum treatment. Other cancers exhibit varying degrees of cytotoxic sensitivity to platinum drugs, as evidenced by tumor regression following initial treatment, but subsequently develop an increasing level of platinum resistance which is manifested as an absence of tumor shrinkage or by frank tumor growth progression or metastases during or following treatment with the platinum drug (i.e., “acquired resistance”). New platinum agents are sought which can effectively kill tumor cells but that are also insensitive or less susceptible to tumor-mediated drug resistance mechanisms that are observed with other platinum agents.
In attempting to solve this problem, one research group (see, Uchiyama, et al., Bull. Chem. Soc. Jpn. 54:181-85 (1981)) has developed cisplatin analogues possessing a nitrile group substituted for each of the amine groups in cisplatin (IUPAC Nomenclature: cis-bisbenzonitriledichloroplatinum(II)). The structural formula for this analog is shown below:

In general, nitrile-ligand based platinum analogs are less polar and more lipophilic (i.e., hydrophobic) than the currently-marketed platinum-based drugs, and thus can be dissolved into less polar solvents including, but not limited to, methylene dichloride, chloroform, acetone, and the like. This greater lipophilicity may allow such analogs to be taken up more readily by cancer cells, by facile diffusion/transport through the lipid bilayer of the cell membrane, than current drugs. Thereby increasing the available concentration of the platinum species that can participate in cytotoxic anti-tumor effects on the DNA within cancer cells.
Additionally, the lone pair of electrons on nitrogen in the nitrile group is located in the sp hybrid orbital, which is closer to the nitrogen nucleus than the sp3 hybrid orbital in the amine ligand. Thus, in platinum analogs, the attraction of the nitrogen nucleus in nitrile ligand for the lone pair of sharing electrons with platinum is greater than in the ammine ligand. This effect results in decreasing the ionic effect between platinum (II) and the leaving group, and increasing the covalent bonding. As a result, the leaving groups are more difficulty to displace by substitution, including aquation, and therefore slower rates of aquation are observed in nitrile N-donor platinum analogs as compared to ammine platinum analogs. It would seem that both the nitrile ligand-based platinum analogs and the intermediates they form upon hydrolysis, possess a slower rate of reaction with naked DNA compared to ammine ligand-based platinum analogs. It is assumed that the slower rate of cross-linkage formation of platinum analogs with DNA bases may be less susceptible to tumor-mediated platinum-DNA repair mechanisms, which is one of the key platinum drug resistance mechanisms. In addition, and equally important from a pharmacological, toxicological, chemical and drug-resistance circumvention mechanistic points of view, the nitrile-, azido- and R—N═N-containing platinum analogs described below are predicted to be substantially less chemically reactive than cisplatin, carboplatin and oxaliplatin. Therefore, these nitrile-, azido- and R—N═N-containing platinum analogs react substantially more slowly with, and thereby avoid unwanted platinum-sulfur and platinum-nitrogen conjugates with, the thiols, disulfides and proteins/peptides present in vivo; specifically the sulfur-containing physiological thiols, disulfides and peptides/amino acids, including but not limited to, glutathione, cysteine, homocysteine, methionine and all other sulfur-containing and imidazole-containing (e.g., histidine), or arginine or lysine di- tri- and larger peptides, that participate in tumor-mediated platinum drug resistance. Therefore, these novel nitrile, azido and other nitrogen ligand-based platinum analogs have potential to circumvent de novo and acquired tumor-mediated cisplatin resistance and kill cancer cells with natural resistance to known platinum drugs. The platinum analogs described below are also thought to permit controlled reduction of the chemical reactivity of the platinum species to such a degree that greater amounts of the platinum species are also delivered intracellularly. This improved delivery of platinum that is available for intracellular DNA adduct formation is mediated by substantial reduction in the amount of non-effective and non-specific reactions of these novel platinum species with proteins and physiological thiols and disulfides, which can attenuate the antitumor effects of conventional platinum analogs.
The same advantages are possessed by cisplatin analogs where one ammine group is replaced with a substituted imine group. These analogs would be capable of hydrogen or electrostatic bonding with DNA. The presumed advantage is that these platinum analogs involve a slower and more controlled reduction of the chemical reactivity of the platinum species to such a degree that greater amounts of the platinum species are delivered intracellularly. This improved delivery of platinum that is available for intracellular DNA adduct formation is mediated by substantial reduction in the amount of non-effective and non-specific reactions of these novel platinum species with proteins and physiological thiols and disulfides (especially glutathione, which is present in large concentrations intracellularly), which can otherwise attenuate the antitumor effects of conventional platinum analogs.
The reaction for cisplatin hydrolysis is illustrated below in Scheme I:
Cisplatin is relatively stable in human plasma, where a high concentration of chloride prevents aquation of cisplatin. Once cisplatin enters a tumor cell, where a much lower concentration of chloride exists, one or both of the chloride ligands of cisplatin is displaced by water to form an aqua active intermediate form (as illustrated above), which in turn can react rapidly with DNA purines to form stable platinum—purine DNA adducts. Another unwanted side reaction of such platinum species is side reactions with physiological thiols and disulfides as well as proteins; such reactions are thought to not be beneficial in killing tumor cells.
Therefore, the development of platinum analogs that do not react as readily with physiological thiols/disulfides and proteins may be markedly more effective against drug-resistant tumors than either cisplatin or the currently utilized analogs.