Reactivity of platinum (II) complexes with (O,S) bidentate ligands towards DNA model systems for cancer treatment

The FDA-approved platinum(II) drugs cisplatin, carboplatin, and oxaliplatin, are the mainstays of present chemotherapy regimens. Nevertheless, there are a variety of severe side effects, including nephrotoxicity, neurotoxicity, ototoxicity, and nausea as well as the problems of drug resistance and dosage limitations. In addition, the current platinum(II) drugs are all administered intravenously, where they can interact with blood components, including human serum albumin (HSA), the most abundant protein in the human bloodstream, that inhibits the action of platinum(II) drugs. In the cytoplasm, the activated drug species bind to cytoplasmic sulfur-containing nucleophiles such as glutathione (GSH), metallothionein, methionine, and other cysteine-rich proteins before the DNA binding. Consequently, these nucleophilic species act as scavengers, decreasing the availability of reactive species and contributing to drug resistance. Therefore, using non-leaving groups that contain soft donor atoms might reduce the affinity of the platinum(II) complexes toward biomolecular sulfur donors. In this work, we present a design of platinum(II) complexes based on antisymbiosis (trans effect), and HSAB principles, with the aim of reducing the affinity of the synthesized platinum(II) complexes towards sulfur-containing nucleophiles, thus reducing the side effects as well as overcoming the drug inhibition and resistance drawbacks.