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。目前铂药物化学的一个令人兴奋的挑战是基于对顺铂- dna相互作用的详细了解，设计新的和更有效的能够克服顺铂耐药性的药物。以顺铂为原料，制备了一种新的双核铂配合物-羟基-吡唑拉托-双（顺）二胺铂（II）)硝酸酯，并用核磁共振（NMR）和红外光谱对其进行了表征。采用高效液相色谱、核磁共振和圆二色光谱研究了双核铂配合物和顺铂与鸟苷-5′-单phasphate、9-乙基鸟嘌呤（9EG）和DNA的反应动力学。双核配合物-9EG加合物的x射线晶体分析结果表明，桥接的吡唑啉配体极惰性，而桥接的羟基配体被两个9EG分子取代，一个9EG分子与一个铂结合，两个9EG分子之间存在堆积现象。两个核酸碱基之间的堆积表明，这种双核复合物与DNA的结合可能只会引起很小的构象变化。由于最近DNA修复酶系统被认为可以识别由铂结合引起的DNA结构扭曲，并在随后的生物处理中去除铂，因此建议修复酶系统不能识别由双核铂复合物结合引起的唯一小的DNA扭曲。双核复合物对顺铂耐药癌细胞的细胞毒性被认为是由于dna修复系统对双核铂复合物结合不敏感。该研究项目的成果有望引领新一代铂类抗癌药物的开发。

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.