Discovery of novel 2-aryl-4-benzoyl-imidazoles targeting the colchicines binding site in tubulin as potential anticancer agents.
Discovery of novel 2-aryl-4-benzoyl-imidazoles targeting the colchicines binding site in tubulin as potential anticancer agents.
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DOI：
10.1021/jm100884b
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发表时间：
2010-10-28
影响因子：
7.3
通讯作者：
Li W
中科院分区：
文献类型：
--
作者：
Chen J;Wang Z;Li CM;Lu Y;Vaddady PK;Meibohm B;Dalton JT;Miller DD;Li W
以2-芳基咪唑-4-甲酰胺（AICA）和4-取代甲基苯甲酰基芳基噻唑（SMART）为基础，通过结构修饰，合成了一系列2-芳基-4-苯甲酰基咪唑（ABI）。活性最高的化合物（5da）的平均IC 50为15.7 nM。ABI类似物具有显著改善的水溶性（5ga为48.9 μg/mL，SMART-1为0.909 μg/mL，紫杉醇为0.137 μg/mL，考布他汀A4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位点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的亲本黑色素瘤癌细胞同样有效。体内实验结果表明，5cb在抑制黑色素瘤异种移植肿瘤生长方面比DTIC更有效。我们的研究结果表明，新的ABI化合物可能被开发，以有效地治疗耐药肿瘤。
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 IC50 of the most active compound (5da) was 15.7 nM. ABI analogs 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 analogs 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.
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影响因子：
7.3
作者：
Lu Y;Li CM;Wang Z;Ross CR 2nd;Chen J;Dalton JT;Li W;Miller DD
通讯作者：
Miller DD
影响因子：
8.8
作者：
Leonessa, F;Green, D;Licht, T;Wright, A;WingateLegette, K;Lippman, J;Gottesman, MM;Clarke, R
通讯作者：
Clarke, R
影响因子：
2.7
作者：
Chen, Jianjun;Wang, Zhao;Li, Wei
通讯作者：
Li, Wei
影响因子：
3.8
作者：
Glomme, A;März, J;Dressman, JB
通讯作者：
Dressman, JB
影响因子：
2.7
作者：
Bellina, Fabio;Cauteruccio, Silvia;Rossi, Renzo
通讯作者：
Rossi, Renzo