Local Distortion of DNA regulated by Dinuclear Platinum Complexes with High Sequence Specificity and Cytotoxicity against Cancer Cells

具有高序列特异性和抗癌细胞细胞毒性的双核铂配合物调节 DNA 局部变形

• 批准号: 09672202
• 负责人: CHIKUMA Masahiko
• 金额: $ 1.79万
• 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 Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09672202/
• 关键词: Cisplatin; Platinum complex; Anticancer platinum complex; Dinuclear complex; Anticancer agent; DNA; Sequence specificity; Bioinorganic chemistry; 抗がん白金錯体

Cisplatin is routinely used for the treatment of a number of tumors. A current exciting challenge in platinum biolnorganic chemistry is to design effective anticancer agents capable of over coming cisplatin resistance bosed on the detailed knowledge of the cisplatin- deoxyribonucleic acid(DNA) interaction, According to recent studies on DNA-lesion repair process in cisplatin resistance cells, ineffectiveness as drug and resistance to cisplatin can be attributed to readiness of recognition of platinum-induced DNA distrotion by repair enzyme systems. The purpose of tlis project is to investigate the interaction of new cinuclear platinum complexes with DNA and to estimate the local distortion of DNA introduced by platinum complexes.The following results were obtained.(1) Anew dinuclear platinum complex, mu-hydroxo-mu-pyrazolato-bis{cis -diammineplatinum(ll)} dinitrate(Complex 1) was prepared and characterized by nuclear magnetic resonance (NMR) and elemental analysis. Complex I binds to D … More NA with bisplatinum structure reserved.(2)Complex 1 was found to bind preferentially to GC pair as well as Cisplatin by determining the amount of platinum bound to DNAs with different GC contents, and to bind to guanine selectively by high performance liquid chromatography and capillary electrophoresis.(3)The difference of melting temperature( DELTA T_m) of DNA in the absence of and in the presence of platinum were measured at various r_b values( r_b = the amount of platinum atom bound to DNA). In the case of Cisplatin, AT_m was negative in the r_b value range 0.01-0.05 and positive in the r_b, range over 0.05. On the other hand, DELTAT_m in Complex 1 was extremely large(20ﾟC) in the r_b range 0.005-0.03. Positive DELTAT_mvalues are attributed to the stabilization of DNA structure based on the formation of interstrand cross links.(4)This study shows the local dstortion of DNA can be regulated by changing the metal- metal cistance in dinuclear platinum complexes and the results obtained from this research promise to lead to the development of new generation of anticancer platinum complexes. Less

顺铂通常用于治疗许多肿瘤。目前铂生物有机化学中令人兴奋的挑战是基于对顺铂-脱氧核糖核酸（DNA）相互作用的详细了解来设计能够克服顺铂抗性的有效抗癌药物。根据最近关于顺铂抗性细胞中DNA损伤修复过程的研究，作为药物无效性和对顺铂的抗性可归因于修复酶系统易于识别铂诱导的DNA破坏。本项目的目的是研究新型双核铂配合物与DNA的相互作用，并估算铂配合物引入DNA的局部畸变。(1)合成了一种新的双核铂配合物μ-羟基-μ-吡唑合-双{顺式二氨合铂（II）}二硝酸盐（配合物1），并通过核磁共振（NMR）和元素分析进行了表征。复合物I与D结合 ...更多信息 NA，保留双铂结构。（2）通过测定不同GC含量的DNA与铂的结合量，发现配合物1与GC对和顺铂都有优先结合，而配合物1与鸟嘌呤有选择性结合。（3）在不同的r_B值（r_B =与DNA结合的铂原子的量）下，测量了不存在和存在铂时DNA的解链温度差（Δ T_m）。顺铂组在r_B = 0.01-0.05范围内AT_m为阴性，r_B = 0.05以上为阳性。另一方面，配合物1中的Δ T_m在r_B 0.005-0.03的范围内非常大（20 ℃）。正Δ T_m值归因于基于链间交联形成的DNA结构的稳定。（4）本研究表明，通过改变双核铂配合物中金属-金属的位置，可以调控DNA的局部损伤，为开发新一代的抗癌铂配合物提供了可能。少

项目成果

千熊 正彦: "Interaction of bisplatinum complex containing μ-hydroxo-μ- pyrazolato structure with GC-rich DNA" J.Inorg.Biochem.67・4. 348-348 (1997)

Masahiko Chikuma：“含有μ-羟基-μ-吡唑结构的双铂复合物与富含GC的DNA的相互作用”J.Inorg.Biochem.67・4（1997）。

千熊 正彦: "Interaction of bisplatinum complex containing μ-hyroxo-μ-pyrazolato structure with GC-rich DNA" J.Inorg.Biochem.67・4. 348-348 (1997)

Masahiko Chikuma：“含有μ-hyroxo-μ-pyrazolato结构的双铂复合物与富含GC的DNA的相互作用”J.Inorg.Biochem.67・4（1997）。

千熊 正彦: "分析化学1 改訂第4版" 南江堂, 314 (1997)

千隈正彦：《分析化学 1 修订版第 4 版》 Nankodo，314 (1997)

千熊 正彦: "分析化学I 改訂第4版" 南江堂, 314 (1997)

Masahiko Chikuma：《分析化学 I 修订版第 4 版》Nankodo，314 (1997)

Masahiko Chikuma, Masahiko Hirai, Seiji Komeda, Yumi Kimura and Kazuhiko Kumakura: "Interaction of bisplatinum complex containing mu-hydroxo-mu-pyrazolato structure with GC-rich DNA" J.Inorg.Biochem.67(4). 348-348 (1997)

Masahiko Chikuma、Masahiko Hirai、Seiji Komeda、Yumi Kimura 和 Kazuhiko Kumakura：“含有 mu-羟基-mu-吡唑结构的双铂复合物与富含 GC 的 DNA 的相互作用”J.Inorg.Biochem.67(4)。