Molecular mechanisms of the biological activity of the anticancer drug elesclomol and its complexes with Cu(II), Ni(II) and Pt(II)
Molecular mechanisms of the biological activity of the anticancer drug elesclomol and its complexes with Cu(II), Ni(II) and Pt(II)
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DOI：
10.1016/j.jinorgbio.2013.04.013
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发表时间：
2013-09-01
影响因子：
3.9
通讯作者：
Hasinoff, Brian B.
中科院分区：
文献类型：
--
作者：
Yadav, Arun A.;Patel, Daywin;Hasinoff, Brian B.
双（硫代酰肼）酰胺艾司氯醇具有极强的抗增殖活性，目前正在作为抗癌药物进行临床试验。艾司氯醇与铜强烈结合，可能通过产生铜介导的氧化应激来发挥其细胞生长抑制作用。合成并表征了艾司氯醇的镍 (II) 和铂 (II) 络合物，以研究这些生物氧化还原惰性金属络合物是否也能抑制细胞生长。镍(II)-艾司洛酚和铂(II)艾司洛酚复合物对人白血病1(562细胞)的效力比铜(II)-艾司洛酚复合物低34倍和1040倍。这些结果支持这样的结论，即艾司洛酚需要氧化还原活性金属才能发挥其细胞生长抑制活性。铜(II)-艾司洛酚还被证明可以在生理条件下有效氧化抗坏血酸。由此产生的铜(I)的再氧化会导致产生破坏性的活性氧。铜(II)-艾司氯醇的X射线晶体结构测定表明，它形成了具有扭曲方形平面结构的1:1中性络合物。在生理条件下，通过分光光度法研究了强铜(II)螯合剂TRIEN与铜(II)-艾司氯醇的竞争反应的动力学和平衡。 elesclomol 结合铜 (II) 的条件稳定性常数比 TRIEN 大 24 倍，因此间接测定了铜 (II)-elesclomol 复合物的对数稳定性常数 (C) 2013 Elsevier Inc。保留所有权利。
The bis(thiohydrazide) amide elesclomol has extremely potent antiproliferative activity and is currently in clinical trials as an anticancer agent. Elesclomol strongly binds copper and may be exerting its cell growth inhibitory effects by generating copper-mediated oxidative stress. Nickel(II) and platinum(II) complexes of elesclomol were synthesized and characterized in order to investigate if these biologically redox inactive metal complexes could also inhibit cell growth. The nickel(II)-elesclomol and platinum(II) elesclomol complexes were 34- and 1040-fold less potent than the copper(II)-elesclomol complex towards human leukemia 1(562 cells. These results support the conclusion that a redox active metal is required for elesclomol to exert its cell growth inhibitory activity. Copper(II)-elesclomol was also shown to efficiently oxidize ascorbic acid at physiological ascorbic acid concentrations. Reoxidation of the copper(I) thus produced would lead to production of damaging reactive oxygen species. An X-ray crystallographic structure determination of copper(II)-elesclomol showed that it formed a 1:1 neutral complex with a distorted square planar structure. The kinetics and equilibria of the competition reaction of the strong copper(II) chelator TRIEN with copper(II)-elesclomol were studied spectrophotometrically under physiological conditions. These results showed elesclomol bound copper(II) with a conditional stability constant 24-fold larger than TRIEN. A log stability constant of 24.2 was thus indirectly determined for the copper(II)-elesclomol complex. (C) 2013 Elsevier Inc. All rights reserved.