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

羟基桥联双核铂配合物形成的动力学和平衡研究及其化学反应性

基本信息

批准号：
03671038
负责人：
CHIKUMA Masahiko
金额：
$ 1.34万
依托单位：
Osaka University of Pharmaceutical Sciences
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1992
项目状态：
已结题

项目摘要

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.

顺铂是目前最有效的抗肿瘤药物之一。它的活性物种一直被认为是顺式二氨基二氢铂(II)离子。它是一种二戊酸，在中性pH区形成二羟基桥联的双核络合物。本研究采用电位法对双核铂(II)络合物的形成进行了动力学和平衡研究，并以脱氧核糖核酸模型5‘-鸟苷-5’-单磷酸为模型，用高效液相色谱、圆二色谱、质子核磁共振等方法研究了铂(II)双核络合物与肿瘤细胞的脱氧核糖核酸的反应。在动力学研究中，通过分析在二氢铂(II)络合物溶液中加入少量氢氧化钾后反应初期氢浓度的变化，计算了观察到的二核络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)络合物的速率常数。羟基桥联双核络合物的形成受胺配体的碱性影响。顺铂衍生的双核络合物与物种的反应性。上述信息有助于了解顺铂的抑瘤作用机制和双核铂(II)配合物的生物活性。