顺式二氯二氨合铂与核苷作用的^(13)C核磁共振研究

STUDY ON THE INTERACTION OF CISPLATIN WITH NUCLEOSIDES BY^(13)C NMR

本文用^(13)C NMR法系统研究了溶液中顺式二氯二氨合铂与胸苷、胞苷、鸟苷和5'-腺嘌呤单核苷酸的作用,确定了不同条件下形成配合物的组成及其分子申铂原子与配体的成键方式。在中性介质中顺铂分别与胸苷、胞苷作用,生成N_(3)配位的顺-[Pt(NH_(3))2(ThyH_(-1))2]和顺-[Pt(NH_(3))2(Cyt)2]^(2+);与鸟苷随摩尔比不同相应生成顺-[Pt(NH_(3))2(N2-Guo)2]2+和[Pt(NH_(3))2(N_(3),N_(1)GuoH_(-1)]nn+,当pH=3和摩尔比为1时,尚有微量[Pt(NH_(3))2(N_(7),O(C6)Guo)]^(2+)生成;在中性介质中顺铂与5'-AMP亦随摩尔比不同,生成顺-[Pt(NH_(3))2(N_(7)-5'-AMP)2]^(2-)或兼生成顺-[Pt(NH_(3))2(N_(7),N_(1)-5'-AMP)]n。根据所得结果讨论了顺铂抗癌作用机制,提出了顺铂可能与DNA同一链上相邻二个鸟嘌呤基上的N_(7)N_(1)键合形成链内交联的新机制。

Interaction of cisplatin with thymidine,cytidine,guanosine and 5’-ade-nosine phosphate in aqueous solution was studied by 13C NMR.The formation of a series of complexes and the site of complexation of nucleo-sides(or nucleotide)to cisplatin in the reaction systems were ascertained,It was found that bonding occurred at N_(3) in thymidine and cytidinp with the formation of complexes,cis-[Pt(NH_(3))2(N_(3)-Thy H_(-1))2]and cis-[Pt(NH_(3))2(N_(3)-Cyt)3]^(3+)In neutral solution,cisplatin reacted with guanosine at N_(7) or/and N_(7)’N_(1) according to the mol ratio of the reactants forming cis-[Pt(NH_(3))2(N_(7)-Guo)3]3+and[Pt(NH_(3))2(N_(7)’N_(1)-GuoH_(-1))]nn+,with a minute amount of[Pt(NH_(3))2(N_(7)’O(C6)-Guo)]2+when pH=3.With 5’AMP,cisplatin formed cis-[Pt(NH_(3))2(N_(7)5’-AMP)2]2-or/and cis-[Pt(NH_(3))3(N_(7),N_(1)-5’-AMP)]n in accordance with the mol ratio of the reactants.On the basis of the above findings,the possible mode of reaction of cisplatin with DNA in the cancer cells is discussed.It is probable that Jntrastrand cross linking is formed between cisplatin and DN A through N_(7),N_(1) atoms of two neighbouring guanines,which may cause lesion of the cancer cells.