Department of Chemistry, University of Kentucky, 505 Rose Street, Lexington, KY 40506, United States.
Department of Chemistry, University of Kentucky, 505 Rose Street, Lexington, KY 40506, United States.
Eur J Med Chem. 2018 Aug 5;156:790-799. doi: 10.1016/j.ejmech.2018.04.044. Epub 2018 Apr 30.
8-Hydroxyquinolines (HQ), including clioquinol, possess cytotoxic properties and are widely used as ligands for metal-based anticancer drug research. The number and identity of substituents on the HQ can have a profound effect on activity for a variety of inorganic compounds. Ruthenium complexes of HQ exhibit radically improved potencies, and operate by a new, currently unknown, mechanism of action. To define structure-activity relationships (SAR), a family of 22 Ru(II) coordination complexes containing mono-, di- and tri-substituted hydroxyquinoline ligands were synthesized and their biological activity evaluated. The complexes exhibited promising cytotoxic activity against a cancer cell line, and the SAR data revealed the 2- and 7-positions as key sites for the incorporation of halogens to improve potency. The Ru(II) complexes potently inhibited translation, as demonstrated by an in-cell translation assay. The effects were seen at 2-15-fold higher concentrations than those required to observe cytotoxicity, suggesting that prevention of protein synthesis may be a primary, but not the exclusive mechanism for the observed cytotoxic activity.
8-羟基喹啉（HQ），包括氯碘羟喹，具有细胞毒性，广泛用作基于金属的抗癌药物研究的配体。HQ 上取代基的数量和种类对各种无机化合物的活性有深远的影响。HQ 的钌配合物表现出明显改善的效力，并且通过一种新的、目前未知的作用机制起作用。为了定义构效关系（SAR），合成了一系列包含单、二和三取代羟基喹啉配体的 22 个 Ru(II)配位配合物，并评估了它们的生物活性。这些配合物对癌细胞系表现出有希望的细胞毒性活性，SAR 数据表明 2-和 7-位是引入卤素以提高效力的关键部位。如细胞内翻译测定所示，Ru(II)配合物强烈抑制翻译。在比观察到细胞毒性所需的浓度高 2-15 倍的浓度下观察到这些效果，这表明蛋白质合成的抑制可能是观察到的细胞毒性活性的主要但不是唯一的机制。
