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Molecular and Cellular Characterization of the Biological Effects of Ruthenium(II) Complexes Incorporating 2-Pyridyl-2-pyrimidine-4-carboxylic Acid
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2012-12-11 , DOI: 10.1021/ja307288s Vanessa Pierroz 1, 2 , Tanmaya Joshi 3 , Anna Leonidova 1 , Cristina Mari 1 , Julia Schur 4 , Ingo Ott 4 , Leone Spiccia 3 , Stefano Ferrari 2 , Gilles Gasser 1
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2012-12-11 , DOI: 10.1021/ja307288s Vanessa Pierroz 1, 2 , Tanmaya Joshi 3 , Anna Leonidova 1 , Cristina Mari 1 , Julia Schur 4 , Ingo Ott 4 , Leone Spiccia 3 , Stefano Ferrari 2 , Gilles Gasser 1
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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 IC(50) 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 calf-thymus 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.
中文翻译：
结合 2-吡啶基-2-嘧啶-4-羧酸的钌 (II) 配合物的生物效应的分子和细胞表征
目前在抗癌研究中研究的绝大多数 Ru 络合物至少部分地通过配体交换发挥其抗增殖活性。然而，近年来，配位饱和和取代惰性的多吡啶基 Ru(II) 化合物已成为潜在的抗癌药物候选者。在这项工作中，我们介绍了两种新型惰性 Ru(II) 配合物的合成和详细表征，即 [Ru(bipy)(2)(Cpp-NH-Hex-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-Hex -COOH = 6-(2-(吡啶-2-基)嘧啶-4-甲酰胺基)己酸；dppz = 双吡啶并[3,2-a:2',3'-c]吩嗪)。3 特别令人感兴趣，因为发现它的 IC(50) 值与该领域的基准标准顺铂相当，对三种癌细胞系和对一种顺铂耐药细胞系的活性优于顺铂本身。然后详细研究了 3 的作用机制，可以证明，虽然 3 通过嵌入与小牛胸腺 DNA 结合，但其诱导的生物学效应不涉及与核 DNA 相关的作用模式。相反，HeLa 细胞中的共聚焦显微镜共定位研究表明，3 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量化进一步相关。此外，如通过两个独立测定确定的，3 在治疗的相对较晚阶段诱导细胞凋亡。可以排除活性氧的产生作为观察到的细胞毒性的原因。
更新日期：2012-12-11
中文翻译：
结合 2-吡啶基-2-嘧啶-4-羧酸的钌 (II) 配合物的生物效应的分子和细胞表征
目前在抗癌研究中研究的绝大多数 Ru 络合物至少部分地通过配体交换发挥其抗增殖活性。然而，近年来，配位饱和和取代惰性的多吡啶基 Ru(II) 化合物已成为潜在的抗癌药物候选者。在这项工作中，我们介绍了两种新型惰性 Ru(II) 配合物的合成和详细表征，即 [Ru(bipy)(2)(Cpp-NH-Hex-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-Hex -COOH = 6-(2-(吡啶-2-基)嘧啶-4-甲酰胺基)己酸；dppz = 双吡啶并[3,2-a:2',3'-c]吩嗪)。3 特别令人感兴趣，因为发现它的 IC(50) 值与该领域的基准标准顺铂相当，对三种癌细胞系和对一种顺铂耐药细胞系的活性优于顺铂本身。然后详细研究了 3 的作用机制，可以证明，虽然 3 通过嵌入与小牛胸腺 DNA 结合，但其诱导的生物学效应不涉及与核 DNA 相关的作用模式。相反，HeLa 细胞中的共聚焦显微镜共定位研究表明，3 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量化进一步相关。此外，如通过两个独立测定确定的，3 在治疗的相对较晚阶段诱导细胞凋亡。可以排除活性氧的产生作为观察到的细胞毒性的原因。
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