发现新型 2-芳基-4-苯甲酰基-咪唑类化合物，靶向微管蛋白上的秋水仙碱结合位点，作为潜在的抗癌药物。
Discovery of novel 2-aryl-4-benzoyl-imidazoles targeting the colchicines binding site in tubulin as potential anticancer agents.
机构信息
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
出版信息
J Med Chem. 2010 Oct 28;53(20):7414-27. doi: 10.1021/jm100884b.
Abstract
A series of 2-aryl-4-benzoyl-imidazoles (ABI) was synthesized as a result of structural modifications based on the previous set of 2-aryl-imidazole-4-carboxylic amide (AICA) derivatives and 4-substituted methoxylbenzoyl-aryl-thiazoles (SMART). The average IC(50) of the most active compound (5da) was 15.7 nM. ABI analogues have substantially improved aqueous solubility (48.9 μg/mL for 5ga vs 0.909 μg/mL for SMART-1, 0.137 μg/mL for paclitaxel, and 1.04 μg/mL for combretastatin A4). Mechanism of action studies indicate that the anticancer activity of ABI analogues is through inhibition of tubulin polymerization by interacting with the colchicine binding site. Unlike paclitaxel and colchicine, the ABI compounds were equally potent against multidrug resistant cancer cells and the sensitive parental melanoma cancer cells. In vivo results indicated that 5cb was more effective than DTIC in inhibiting melanoma xenograph tumor growth. Our results suggest that the novel ABI compounds may be developed to effectively treat drug-resistant tumors.
摘要
一系列 2-芳基-4-苯甲酰基-咪唑（ABI）是基于之前的一组 2-芳基-咪唑-4-甲酰胺（AICA）衍生物和 4-取代甲氧基苯甲酰基-芳基噻唑（SMART）进行结构修饰得到的。最活跃化合物（5da）的平均 IC50为 15.7 nM。ABI 类似物的水溶性有显著提高（5ga 的溶解度为 48.9 μg/mL，而 SMART-1 的溶解度为 0.909 μg/mL，紫杉醇的溶解度为 0.137 μg/mL，康普瑞汀 A4 的溶解度为 1.04 μg/mL）。作用机制研究表明，ABI 类似物的抗癌活性是通过与秋水仙碱结合部位相互作用抑制微管蛋白聚合。与紫杉醇和秋水仙碱不同，ABI 化合物对多药耐药癌细胞和敏感亲本黑素瘤癌细胞同样有效。体内实验结果表明，5cb 抑制黑色素瘤异种移植肿瘤生长的效果优于 DTIC。我们的结果表明，新型 ABI 化合物可能被开发用于有效治疗耐药肿瘤。
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