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首页> 外文期刊>Chemistry: A European journal >Nucleotide Binding Preference of the Monofunctional Platinum Anticancer-Agent Phenanthriplatin
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Nucleotide Binding Preference of the Monofunctional Platinum Anticancer-Agent Phenanthriplatin

机译：单官能铂抗癌剂苯并铂的核苷酸结合偏好

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摘要

The monofunctional platinum anticancer agent phenanthriplatin generates covalent adducts with the purine bases guanine and adenine. Preferential nucleotide binding was investigated by using a polymerase stop assay and linear DNA amplification with a 163-base pair DNA double helix. Similarly to cisplatin, phenanthriplatin forms the majority of adducts at guanosine residues, but significant differences in both the number and position of platination sites emerge when comparing results for the two complexes. Notably, the monofunctional complex generates a greater number of polymerase-halting lesions at adenosine residues than does cisplatin. Studies with 9-methyladenine reveal that, under abiological conditions, phenanthriplatin binds to the N-1 or N-7 position of 9-methyladenine in approximately equimolar amounts. By contrast, comparable reactions with 9-methylguanine afforded only the N-7-bound species. Both of the 9-methyladenine linkage isomers (N-1 and N-7) exist as two diastereomeric species, arising from hindered rotation of the aromatic ligands about their respective platinum-nitrogen bonds. Eyring analysis of rate constants extracted from variable-temperature NMR spectroscopic data revealed that the activation energies for ligand rotation in the N-1-bound platinum complex and the N-7-linkage isomers are comparable. Finally, a kinetic analysis indicated that phenanthriplatin reacts more rapidly, by a factor of eight, with 9-methylguanine than with 9-methyladenine, suggesting that the distribution of lesions formed on double-stranded DNA is kinetically controlled. In addition, implications for the potent anticancer activity of phenanthriplatin are discussed herein.
机译：单功能铂抗癌药菲铂与嘌呤碱基鸟嘌呤和腺嘌呤产生共价加合物。通过使用聚合酶终止试验和具有163个碱基对的DNA双螺旋的线性DNA扩增研究了优先核苷酸结合。与顺铂相似，邻铂在鸟苷残基上形成大多数加合物，但是当比较两种复合物的结果时，在铂化位点的数量和位置上都存在显着差异。值得注意的是，与顺铂相比，单功能复合物在腺苷残基上产生了更多的聚合酶终止损伤。对9-甲基腺嘌呤的研究表明，在非生物条件下，菲铂与9-甲基腺嘌呤的N-1或N-7位置结合的摩尔量大致相等。相比之下，与9-甲基鸟嘌呤的可比反应仅提供了与N-7结合的物质。 9-甲基腺嘌呤键的两个异构体（N-1和N-7）都以两个非对映异构体的形式存在，这是由于芳香族配体绕其各自的铂-氮键旋转受阻所致。从可变温度NMR光谱数据中提取的速率常数的Eyring分析显示，在N-1键合的铂络合物和N-7键异构体中，配体旋转的活化能可比。最终，动力学分析表明，与9-甲基腺嘌呤相比，菲铂与9-甲基鸟嘌呤的反应速度提高了8倍，这表明在双链DNA上形成的损伤分布受到动力学控制。另外，本文讨论了对菲咯啉的有效抗癌活性的意义。

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