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

顺铂通常用于治疗多种肿瘤。基于对顺铂-脱氧核糖核酸（DNA）相互作用的详细了解，设计能够克服顺铂耐药的有效抗癌药物是目前铂生物有机化学领域的一个令人兴奋的挑战。根据最近对顺铂耐药细胞DNA损伤修复过程的研究，作为药物无效和对顺铂耐药可归因于修复酶系统对铂诱导的DNA分布的识别。该项目的目的是研究新的核铂配合物与DNA的相互作用，并估计铂配合物引入DNA的局部畸变。得到了以下结果：(1)制备了新的双核铂配合物-mu-羟基-mu-吡唑拉托-双{顺式-二胺铂（ll）}硝酸酯（配合物1），并用核磁共振（NMR）和元素分析对其进行了表征。配合物I与保留双铂结构的多NA结合。(2)通过测定不同GC含量dna上铂的结合量，发现配合物1优先与GC对和顺铂结合；通过高效液相色谱和毛细管电泳，发现配合物1与鸟嘌呤选择性结合。(3)在不同的r_b值（r_b =铂原子与DNA的结合量）下，测定了无铂和有铂时DNA的熔化温度（DELTA T_m）的差异。对于顺铂，AT_m在r_b值0.01 ~ 0.05范围内为阴性，r_b值大于0.05范围内为阳性。另一方面，配合物1中的DELTAT_m在r_b范围0.005-0.03内非常大（20‰C）。正的deltat_mvalue归因于基于链间交联形成的DNA结构的稳定。(4)本研究表明，DNA的局部畸变可以通过改变双核铂配合物中的金属-金属物质来调节，本研究结果有望引导新一代抗癌铂配合物的开发。少

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