发现具有强效抗增殖活性的 4-芳基-2-苯甲酰基-咪唑啉作为微管聚合抑制剂。
Discovery of 4-Aryl-2-benzoyl-imidazoles as tubulin polymerization inhibitor with potent antiproliferative properties.
机构信息
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
出版信息
J Med Chem. 2013 Apr 25;56(8):3318-29. doi: 10.1021/jm4001117. Epub 2013 Apr 9.
Abstract
A series of 4-aryl-2-benzoyl-imidazoles were designed and synthesized based on our previously reported 2-aryl-4-benzoyl-imidazole (ABI) derivatives. The new structures reversed the aryl group and the benzoyl group of previous ABI structures and were named as reverse ABI (RABI) analogues. RABIs were evaluated for biological activity against eight cancer cell lines including multidrug-resistant cancer cell lines. In vitro assays indicated that several RABI compounds had excellent antiproliferative properties, with IC50 values in the low nanomolar range. The average IC50 of the most active compound 12a is 14 nM. In addition, the mechanism of action of these new analogues was investigated by cell cycle analysis, tubulin polymerization assay, competitive mass spectrometry binding assay, and molecular docking studies. These studies confirmed that these new RABI analogues maintain their mechanisms of action by disrupting tubulin polymerization, similar to their parental ABI analogues.
摘要
基于我们之前报道的 2-芳基-4-苯甲酰基-咪唑（ABI）衍生物，设计并合成了一系列 4-芳基-2-苯甲酰基-咪唑。新结构将之前 ABI 结构中的芳基和苯甲酰基进行了反转，被命名为反转 ABI（RABI）类似物。对这些 RABI 化合物进行了针对包括多药耐药癌细胞系在内的八种癌细胞系的生物活性评估。体外实验表明，几种 RABI 化合物具有优异的抗增殖特性，IC50 值在纳摩尔低浓度范围内。最活跃的化合物 12a 的平均 IC50 为 14 nM。此外，通过细胞周期分析、微管蛋白聚合测定、竞争性质谱结合测定和分子对接研究，研究了这些新类似物的作用机制。这些研究证实，这些新的 RABI 类似物通过破坏微管蛋白聚合来保持其作用机制，类似于其母体 ABI 类似物。
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