Molecular and Cellular Characterization of the Biological Effects of Ruthenium(II) Complexes Incorporating 2-Pyridyl-2-pyrimidine-4-carboxylic Acid
Molecular and Cellular Characterization of the Biological Effects of Ruthenium(II) Complexes Incorporating 2-Pyridyl-2-pyrimidine-4-carboxylic Acid
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DOI：
10.1021/ja307288s
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发表时间：
2012-12-19
影响因子：
15
通讯作者：
Gasser, Gilles
中科院分区：
文献类型：
--
作者：
Pierroz, Vanessa;Joshi, Tanmaya;Gasser, Gilles
目前在抗癌研究中研究的绝大多数Ru配合物，至少部分是通过配体交换发挥其抗增殖活性的。然而，近年来，配位饱和和取代惰性多吡啶基Ru（II）化合物已成为潜在的抗癌候选药物。在这项工作中，我们提出了两种新型惰性Ru（II）配合物的合成和详细表征，即[Ru(bipy)(2)(cpp - nh - hexx - cooh)](2+)(2)和[Ru(dppz)(2)(CppH)](2+) (3) (bipy = 2,2'-联吡啶；CppH = 2-（2'-吡啶基）嘧啶-4-羧酸；cpp - nh - hexx - cooh = 6-（2-（吡啶-2-基）嘧啶-4-羧胺）己酸；DPPZ =二吡啶多[3,2-a:2',3'-c]吩那嗪)。3是特别有趣的，因为它被发现在三种癌细胞系上具有与顺铂相当的IC50值，顺铂是该领域的基准标准，并且在一种顺铂耐药细胞系上具有比顺铂本身更好的活性。对3的作用机制进行了详细的研究，结果表明，虽然3通过嵌入方式与胸腺DNA结合，但其诱导的生物学效应并不涉及与核DNA相关的作用方式。相反，在HeLa细胞中的共聚焦显微镜共定位研究表明，其中3个特异性靶向线粒体。这与使用高分辨率原子吸收光谱法的钌定量进一步相关。此外，通过两项独立实验确定，3在相对较晚的治疗阶段诱导细胞凋亡。可以排除活性氧的产生是所观察到的细胞毒性的原因。结果表明，早在引入HeLa后2 h，线粒体膜电位就受到了3的损害，并且随着时间的增加，线粒体膜电位受到的损害更大。
A great majority of the Ru complexes currently studied in anticancer research exert their antiproliferative activity, at least partially, through ligand exchange. In recent years, however, coordinatively saturated and substitutionally inert polypyridyl Ru(II) compounds have emerged as potential anticancer drug candidates. In this work, we present the synthesis and detailed characterization of two novel inert Ru(II) complexes, namely, [Ru(bipy)(2)(Cpp-NH-Hex-COOH)](2+) (2) and [Ru(dppz)(2)(CppH)](2+) (3) (bipy = 2,2'-bipyridine; CppH = 2-(2'-pyridyl)pyrimidine-4-carboxylic acid; Cpp-NH-Hex-COOH = 6-(2-(pyridin-2-yl)pyrimidine-4-carboxamido)hexanoic acid; dppz = dipyrido[3,2-a:2',3'-c]phenazine). 3 is of particular interest as it was found to have IC50 values comparable to cisplatin, a benchmark standard in the field, on three cancer cell lines and a better activity on one cisplatin-resistant cell line than cisplatin itself. The mechanism of action of 3 was then investigated in detail and it could be demonstrated that, although 3 binds to calfthymus DNA by intercalation, the biological effects that it induces did not involve a nuclear DNA related mode of action. On the contrary, confocal microscopy colocalization studies in HeLa cells showed that 3 specifically targeted mitochondria. This was further correlated by ruthenium quantification using High-resolution atomic absorption spectrometry. Furthermore, as determined by two independent assays, 3 induced apoptosis at a relatively late stage of treatment. The generation of reactive oxygen species could be excluded as the cause of the observed cytotoxicity. It was demonstrated that the mitochondrial membrane potential in HeLa was impaired by 3 as early as 2 h after its introduction and even more with increasing time.