School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, Wales CF10 3NB, UK.
Sharjah Institute for Medical Research, College of Pharmacy, University of Sharjah, P.O. Box 27272, Sharjah, UAE.
Molecules. 2019 Apr 2;24(7):1274. doi: 10.3390/molecules24071274.
The Bcl-2 protein has been studied as an anticancer drug target in recent years, due to its gatekeeper role in resisting programmed cancer cell death (apoptosis), and the design of BH3 domain mimetics has led to the clinical approval of Venetoclax (ABT-199) for the treatment of chronic lymphocytic leukaemia. In this work we extend our previous studies on the discovery of indole-based heterocycles as Bcl-2 inhibitors, to the identification of quinolin-4-yl based oxadiazole and triazole analogues. Target compounds were readily synthesized via a common aryl-substituted quinolin-4-carbonyl--arylhydrazine-1-carbothioamide () intermediate, through simple variation of the basic cyclisation conditions. Some of the quinoline-based oxadiazole analogues (e.g. compound ) were found to exhibit sub-micromolar anti-proliferative activity in Bcl-2-expressing cancer cell lines, and sub-micromolar IC activity within a Bcl2-Bim peptide ELISA assay. The Bcl-2 targeted anticancer activity of was further rationalised via computational molecular modelling, offering possibilities to extend this work into the design of further potent and selective Bcl-2 inhibitory heteroaromatics with therapeutic potential.
近年来，Bcl-2 蛋白已被研究作为一种抗癌药物靶点，因其在抵抗程序性癌细胞死亡（细胞凋亡）中起关键作用，并且 BH3 结构域类似物的设计已导致 Venetoclax（ABT-199）被批准用于治疗慢性淋巴细胞白血病。在这项工作中，我们扩展了以前关于发现吲哚为基础的杂环作为 Bcl-2 抑制剂的研究，以鉴定喹啉-4-基噁二唑和三唑类似物。目标化合物可通过共同的芳基取代的喹啉-4-羰基-芳基肼-1-碳硫酰胺（）中间体制备，通过简单改变基本环化条件。一些基于喹啉的噁二唑类似物（例如化合物）在表达 Bcl-2 的癌细胞系中表现出亚微摩尔的抗增殖活性，并且在 Bcl2-Bim 肽 ELISA 测定中具有亚微摩尔的 IC 活性。通过计算分子建模进一步合理化了 Bcl-2 靶向抗癌活性，为进一步设计具有治疗潜力的强效和选择性 Bcl-2 抑制性杂芳族化合物提供了可能性。
