Binding Mode of New Dinuclear Platinum Complexes Effective against Cisplatin-resistant Cancer Cells with DNA

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Cisplatin, a DNA-damging agent, is one of the most widely used anticancer drugs. A current exciting challenge in platinum medicinal chemistry is to design new and more effective agents capable of overcoming cisplatin resistance based on the detailed knowledge of the cisplatin-DNA interaction. A new dinuclear platinum complex, mu-hydroxo-mu-pyrazolato-bis {cis-diammineplatinum (II) } dinitrate derived from cisplatin was prepared and characterized by nuclear magnetic resonance (NMR) and infrared spectroscopies. The reaction of the dinuclear platinum complex and cisplatin with guanosine-5'-mono-phasphate, 9-ethylguanine (9EG), and DNA was investigated kinetically by high performance liquid chromatography and NMR and circular dichromism spectrocsopies. The results of X-ray crystallographic analysis of the dinuclear complex-9EG adduct show that the bridged pyrazolato ligand is extremely inert while the bridged hydroxo ligand is substituted with two 9EG molecules and that one 9EG molecule binds to one platinum, and that stacking between the two 9EG molecules is observed. The presence of stacking between two nucleic acid bases suggests that the binding of this dinuclear complex to DNA may introduce only small conformational change. Since recently DNA-repair enzyme systems have been considered to recognize structural distortions of DNA introduced by platinum binding and to remove the platinums in the consequent biological processing, the only small DNA-distortion derived by the dinuclear platinum complex binding is suggested not to be recognized by the repair-enzyme systems. Cytotoxicity of the dinuclear complex against cisplatin-resistant cancer cell lines is considered to be attributted to insensitiveness of DNA-repair system to the dinuclear platinum complex binding.The results obtained from this research project promise to lead to the development of new generation of platinum anticancer drugs.