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

顺铂是治疗多种肿瘤的常规药物。目前铂生物有机化学领域的一个令人兴奋的挑战是设计能够克服顺铂耐药的有效抗癌药物。基于对顺铂-脱氧核糖核酸(DNA)相互作用的详细了解，根据最近对顺铂耐药细胞DNA损伤修复过程的研究，药物失效和顺铂耐药可归因于修复酶系统对铂诱导的DNA损伤的识别能力。TLIS项目的目的是研究新的银核铂配合物与DNA的相互作用，并估计铂配合物对DNA的局部扭曲作用。获得了以下结果：(1)合成了一种新的双核铂配合物：mU-羟基-mU-吡唑烷-双{顺式亚胺铂(11)}二硝酸酯(化合物1)，并通过核磁共振和元素分析对其进行了表征。复合体I与D…结合(2)通过测定不同GC含量的DNA上的铂结合量，发现化合物1优先与GC对和顺铂结合，并通过高效液相色谱和毛细管电泳法选择性地与鸟嘌呤结合。(3)测定了不同rb值(rb=铂原子与DNA结合的量)下DNA在无铂和有铂存在下的熔融温度差(Delta Tm)。顺铂的AT_m在r_b值0.01~0.05范围内为负值，在r_b值范围内为正值，范围在0.05以上。另一方面，络合物1的DELTAT_m在0.005-0.03Rb范围内非常大(20ﾟC)。正的DELTAT_m值归因于基于形成链间交联键的DNA结构的稳定。(4)本研究表明，通过改变双核铂配合物中的金属-金属含量可以调节DNA的局部储存，这一研究结果有望为新一代抗癌铂配合物的开发奠定基础。较少

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