Kinetic and Equilibrium Studies on Formation of Hydroxo-bridged Dinuclear Platinum Complexes and Their Chemical Reactivities

顺铂是最有效的抗肿瘤药物之一。其活性物质被认为是顺-二胺二氢铂（II）离子。它是一种二质子酸，在中性pH区形成二羟基桥接双核络合物。本课题采用电位法对双核铂（II）配合物形成的动力学和平衡进行了研究，并采用高效液相色谱法、圆二色光谱法和质子核磁共振光谱法研究了双核配合物与鸟苷-5′-单磷酸作为模型的脱氧核糖核酸反应，而鸟苷-5′-单磷酸是铂配合物在肿瘤细胞中可能的靶点。在动力学研究中，通过分析在二氢铂（II）配合物溶液中加入少量氢氧化钾后反应初期氢浓度的变化，计算了观察到的双核配合物形成的二级速率常数。测定了几种含乙二胺及其衍生物的铂（II）配合物的反应速率常数。羟基桥接双核配合物的形成被发现受胺配体的碱度的影响。顺铂衍生的双核配合物与物种的反应性。含5′-GMP的单羟基桥接铂配合物的形成被认为是前一反应的中间产物。上述信息有助于了解顺铂的肿瘤抑制作用机制以及双核铂（II）配合物的生物活性。

Ciplatin is one of the most active antitumor drugs. Its active species has been believed to be cis-diamminediaquaplatinum(II) ion. It is a diprotic acid and forms a dihydroxo-bridged dinuclear complex in neutral pH region. In this research project, kinetic and equilibrium studies on the formation of the dinuclear platinum(II) complexes were carried out by potentiometry, and the reaction of dinuclear complexes with guanosine-5'-monophosphate as a model of deoxyribonucleic acid, which is the likely target for platinum complexes in tumor cells, was investigated by high-performance liquid chromatography, circular dichromism spectrometry, and proton nuclear magnetic resonance spectrometry.In the kinetic sutudy, the observed second order rate constants for the dinuclear complex formation were calculated from the analysis of the hydrogen concentration variation at the early stage of the reaction after a small amount of potassium hydroxide was added to the solution of diaquaplatinum(II) complexes. The rate constants for several platinum(II) complexes containing ethylendiamine and its derivatives were determined. The formation of the hydroxo-bridged dinuclear complexes is found to be influenced by the basicity of amine ligands.The reactivities of the dinuclear complex derived from cisplatin with species. The formation of monohydroxo-bridged platinum complex containing 5' -GMP was suggested as an intermediate in the former reaction.The above information is useful to understand the mechanism of the tumor inhibitory action of cisplatin and the biological activities of the dinuclear platinum(II) complexes.