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首页> 外文期刊>Metallomics. integrated biometal science >Metallomics for drug development: a further insight into intracellular activation chemistry of a ruthenium(III)-based anticancer drug gained using a multidimensional analytical approach
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Metallomics for drug development: a further insight into intracellular activation chemistry of a ruthenium(III)-based anticancer drug gained using a multidimensional analytical approach

机译：用于药物开发的金属组学：使用多维分析方法获得的基于钌（III）的抗癌药的细胞内活化化学的进一步见解

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The mechanism by which the most relevant ruthenium anticancer drugs are activated in tumors to commence their tumor-inhibiting action remains one of the challenging research tasks of present-day metallomics. This contribution aims to capture and identify eventually more reactive species of one of two bis-indazole tetrachloridoruthenate(III) compounds that are progressing in clinical trials. In view of the fact that the transport of ruthenium into cancer cells is governed by transferrin receptors, the susceptibility of the Ru drug adduct with holo-transferrin to exposure by glutathione and ascorbic acid (at their cancer cytosol concentrations) was studied by inductively coupled plasma mass spectrometry (ICP-MS), following isolation of the reaction products by ultrafiltration. Next, capillary electrophoresis coupled to ICP-MS was applied to monitor changes in the Ru speciation both under simulated cancer cytosol conditions and in real cytosol and to assign the charge state of novel metal species. The latter were identified by using tandem electrospray ionization MS in the respective ion mode. The formation of ruthenium(II) species was for the first time revealed, in which the central metal is coordinated by the reduced (GSH) or the oxidized (GSSG) form of glutathione, i.e. [Ru(II)HindCl(4)(GSH)](2-) and [Ru(II)HindCl(4)(GSSG)](2-), respectively (Hind = indazole). Ascorbic acid released the ruthenium functionality from the protein-bound form in a different way, the products of adduct cleavage containing aqua ligands. Distribution of low-molecular mass species of Ru in human cytosol was found to have very much in common with the ruthenium speciation assayed under simulated cytosol conditions.
机译：最相关的钌抗癌药在肿瘤中被激活以开始其肿瘤抑制作用的机制仍然是当今冶金学中具有挑战性的研究任务之一。该贡献旨在捕获和鉴定最终在临床试验中正在发展的两种双吲哚四氯代钌酸酯（III）化合物中更具反应性的物种。鉴于钌向癌细胞的转运受转铁蛋白受体控制，因此通过电感耦合血浆研究了Ru药物加合物与全运铁蛋白对谷胱甘肽和抗坏血酸（在其癌细胞溶质浓度下）接触的敏感性。质谱（ICP-MS），然后通过超滤分离反应产物。接下来，将毛细管电泳与ICP-MS耦合以监测Ru形态在模拟的癌症细胞溶胶条件下和实际细胞溶胶中的变化，并指定新型金属物质的电荷状态。后者通过在相应离子模式下使用串联电喷雾电离质谱仪进行鉴定。首次揭示了钌（II）物种的形成，其中中心金属由谷胱甘肽的还原型（GSH）或氧化型（GSSG）配位，即[Ru（II）HindCl（4）（GSH） ）]（2-）和[Ru（II）HindCl（4）（GSSG）]（2-）（Hind =吲唑）。抗坏血酸以一种不同的方式从蛋白质结合形式释放出钌官能团，其中的加合物裂解产物含有水配体。发现钌在人细胞质中的低分子量物质分布与在模拟细胞质条件下测定的钌形态有很多共同点。

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