Design, Synthesis, and Biological Evaluation of Stable Colchicine-Binding Site Tubulin Inhibitors 6-Aryl-2-benzoyl-pyridines as Potential Anticancer Agents.
Design, Synthesis, and Biological Evaluation of Stable Colchicine-Binding Site Tubulin Inhibitors 6-Aryl-2-benzoyl-pyridines as Potential Anticancer Agents.
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DOI：
10.1021/acs.jmedchem.1c00715
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发表时间：
2021-08-26
影响因子：
7.3
通讯作者：
Li, Wei
中科院分区：
文献类型：
--
作者：
Chen, Hao;Deng, Shanshan;Albadari, Najah;Yun, Mi-Kyung;Zhang, Sicheng;Li, Yong;Ma, Dejian;Parke, Deanna N.;Yang, Lei;Seagroves, Tiffany N.;White, Stephen W.;Miller, Duane D.;Li, Wei
我们之前报道了一种有效的微管蛋白抑制剂CH-2-77。在本研究中，我们通过封闭代谢不稳定部位来优化CH-2-77的结构，并合成了一系列CH-2-77类似物。两个化合物，40a和60c，在保持效力的同时，将CH-2-77的代谢稳定性提高了3-4倍(人微粒体中分别为46.8和29.4分钟比10.8分钟)。我们测定了微管蛋白与40a和60c的高分辨X射线晶体结构，证实了它们直接结合在秋水仙素结合部位。在体外，60c通过抑制微管蛋白聚合维持其作用模式，并对P-糖蛋白介导的多药耐药和紫杉醇耐药有效。在体内，60c对紫杉醇耐药的A375/TxR异种移植瘤模型显示出很强的抑制肿瘤生长和转移的作用，且没有明显的毒性。综上所述，本工作表明60C是一种很有前景的先导化合物，有望作为一种潜在的抗癌剂进行开发。
We previously reported a potent tubulin inhibitor CH-2-77. In this study, we optimized the structure of CH-2-77 by blocking metabolically labile sites and synthesized a series of CH-2-77 analogues. Two compounds, 40a and 60c, preserved the potency while improving the metabolic stability over CH-2-77 by 3- to 4-fold (46.8 and 29.4 vs 10.8 min in human microsomes). We determined the high-resolution X-ray crystal structures of 40a (resolution 2.3 Å) and 60c (resolution 2.6 Å) in complex with tubulin and confirmed their direct binding at the colchicine-binding site. In vitro, 60c maintained its mode of action by inhibiting tubulin polymerization and was effective against P-glycoprotein-mediated multiple drug resistance and taxol resistance. In vivo, 60c exhibited a strong inhibitory effect on tumor growth and metastasis in a taxol-resistant A375/TxR xenograft model without obvious toxicity. Collectively, this work showed that 60c is a promising lead compound for further development as a potential anticancer agent.
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影响因子：
5.1
作者：
Baig, Mirza Feroz;Nayak, V. Lakshma;Kamal, Ahmed
通讯作者：
Kamal, Ahmed
影响因子：
3.5
作者：
Mahindroo, Neeraj;Connelly, Michele C.;Punchihewa, Chandanamali;Yang, Lei;Yan, Bing;Fujii, Naoaki
通讯作者：
Fujii, Naoaki
影响因子：
11.2
作者：
Li CM;Wang Z;Lu Y;Ahn S;Narayanan R;Kearbey JD;Parke DN;Li W;Miller DD;Dalton JT
通讯作者：
Dalton JT
影响因子：
5.6
作者：
Nawrotek, Agata;Knossow, Marcel;Gigant, Benoit
通讯作者：
Gigant, Benoit
DOI：
10.2174/138620708784911429
发表时间：
2008-07-01
影响因子：
1.8
作者：
Di, Li;Kerns, Edward H.;Carter, Guy T.
通讯作者：
Carter, Guy T.