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

顺铂是一种DNA损伤剂，是应用最广泛的抗癌药物之一。目前铂药物化学中令人兴奋的挑战是基于顺铂-DNA相互作用的详细知识设计能够克服顺铂耐药性的新的和更有效的药剂。合成了一种新的双核铂配合物μ-羟基-μ-吡唑并双{顺式-二氨合铂（II）}二硝酸盐，并通过核磁共振（NMR）和红外光谱对其结构进行了表征。用高效液相色谱、核磁共振和圆二色谱研究了双核铂配合物和顺铂与鸟苷-5 '-单磷酸、9-乙基鸟嘌呤（9 EG）和DNA的反应动力学。X射线晶体学分析结果表明，桥联吡唑基配体是惰性的，桥联羟基配体被两个9 EG分子取代，一个9 EG分子与一个铂原子结合，两个9 EG分子之间存在堆积现象。两个核酸碱基之间的堆积的存在表明，这种双核复合物与DNA的结合可能只会引入很小的构象变化。由于最近的DNA修复酶系统已被认为是认识到由铂结合引入的DNA的结构畸变，并在随后的生物处理中除去铂，双核铂络合物结合所产生的唯一小的DNA畸变被认为是不被修复酶系统所识别的。双核铂配合物对顺铂耐药细胞系的细胞毒性被认为是由于DNA修复系统对双核铂配合物的结合不敏感。

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.