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首页> 外文期刊>Dalton transactions: An international journal of inorganic chemistry >Discovery of a strongly apoptotic ruthenium complex through combinatorial coordination chemistry
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Discovery of a strongly apoptotic ruthenium complex through combinatorial coordination chemistry

机译：通过组合配位化学发现强凋亡钌络合物

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摘要

A strategy for combinatorial parallel coordination chemistry is introduced that provides access to libraries of tris-heteroleptic ruthenium complexes in an economical fashion. Using this method, a library of 560 constitutionally unique, monocationic ruthenium complexes was synthesized, followed by a screening for anticancer activity and resulting in the identification of three hits with promising cytotoxic properties in HeLa cancer cells. A subsequent structure-activity relationship led to the discovery of the surprisingly simple anticancer complex [Ru(tBu_2bpy)_2(phox)]PF_6 (complex 1), with tBu_2bpy = 4,4′-di-tert-buty-2,2′- bipyridine and Hphox = 2-(2′-hydroxyphenyl)oxazoline, displaying an LC_(50) value in HeLa cells of 1.3 μM and 0.3 μM after incubation for 24 and 72 h, respectively. Complex 1 also shows remarkable antiproliferative and apoptotic properties at submicromolar concentrations in more clinically relevant Burkitt-like lymphoma cells. A reduction of the mitochondrial membrane potential by 1 indicates the involvement of the intrinsic pathway of programmed cell death. Further investigations reveal that 1 requires caspase-3 for the induction of apoptosis but is insensitive to the proapoptotic and antiapoptotic proteins Smac and Bcl-2, respectively.
机译：引入了一种组合平行配位化学的策略，该策略以经济的方式提供了对三杂合钌配合物库的访问。使用这种方法，合成了560个组成独特的单阳离子钌络合物的文库，然后筛选了抗癌活性，并鉴定了在HeLa癌细胞中具有有希望的细胞毒性的三个命中。随后的结构-活性关系导致发现了令人惊讶的简单的抗癌复合物[Ru（tBu_2bpy）_2（phox）] PF_6（复合物1），其中tBu_2bpy = 4,4'-di-tert-buty-2,2' -联吡啶和Hphox = 2-（2'-羟基苯基）恶唑啉，在孵育24小时和72小时后，在HeLa细胞中的LC_（50）值分别为1.3μM和0.3μM。在与临床相关的伯基特样淋巴瘤细胞中，亚微摩尔浓度的复合物1也显示出显着的抗增殖和凋亡特性。线粒体膜电位降低1表示参与程序性细胞死亡的内在途径。进一步的研究表明1需要caspase-3诱导细胞凋亡，但分别对促凋亡和抗凋亡蛋白Smac和Bcl-2不敏感。

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