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

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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