Multiple Recognition of DNA by dinuclear platinum complexes with effective cell growth inhibition in cisplatin resistant cell lines

铂配合物的抗肿瘤活性和细胞耐药机制都与铂配合物与DNA的配位结合方式有关。多核复合体有望以不同的方式与DNA相互作用，并具有不同于单核复合体的作用机制，如顺铂，顺铂是最有效的抗肿瘤药物之一。为了寻找活性更高的铂配合物，克服顺铂的耐药性，我们以吡唑类似物为桥联配体，合成了双核铂(II)阳离子配合物[{cis-铂(NH_3)_2}_2(μ-吡唑)(μ-OH)](NO_3)_2(AMPZ)及其衍生物。这些铂配合物对顺铂耐药的肿瘤细胞株有一定的抑制作用。AMPZ可与DNA发生共价和非共价相互作用。在本研究中，我们重点研究了AMPZ与DNA的非共价结合模式，并用多种方法研究了AMPZ与DNA的非共价结合模式。AMPZ的抗肿瘤活性是否归因于AMPZ与DNA的非共价结合，目前尚不清楚。

Both mechanisms of anti-tumor activity and cellular resistance to platinum complexes are believed to be related with coordination binding mode of platinum complexes with DNA. Polynuclear complexes are expected to interact variously with DNA and to have different mechanism of action from that of mononuclear complexes such as cisplatin, one of the most effective anti-tumor agents. In an attempt to search for more active platinum complexes and to overcome cisplatin resistance, we have developed a dinuclear platinum(II) cation complex, [{cis-Pt(NH_3)_2}_2(μ-pyrazolato) (μ-OH)](NO_3)_2 (AMPZ) and its derivatives using pyrazole analogues as bridging ligands. These platinum complexes were effective to cisplatin-resistant tumor cell lines. AMPZ was found to interact covalently and non-covalently with DNA. In this study we focused to non-covalent binding mode of AMPZ with DNA and investigated with various methods.The non-covalent binding mode of AMPZ with DNA has been found to an electrostatic interaction. It remains to be elucidated whether the anti-tumor activity of AMPZ is attributed to the non-covalent binding of AMPZ with DNA or not.