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Design, Synthesis, and Biological Evaluation of 1‑Methyl-1,4-dihydroindeno[1,2‑c]pyrazole Analogues as Potential Anticancer Agents Targeting Tubulin Colchicine Binding Site

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journal contribution
posted on 12.05.2016, 00:00 by Yan-Na Liu, Jing-Jing Wang, Ya-Ting Ji, Guo-Dong Zhao, Long-Qian Tang, Cheng-Mei Zhang, Xiu-Li Guo, Zhao-Peng Liu
By targeting a new binding region at the interface between αβ-tubulin heterodimers at the colchicine binding site, we designed a series of 7-substituted 1-methyl-1,4-dihydroindeno­[1,2-c]­pyrazoles as potential tubulin polymerization inhibitors. Among the compounds synthesized, 2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1,4-dihydroindeno­[1,2-c]­pyrazol-7-yloxy)­acetamide 6a and 2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1,4-dihydroindeno­[1,2-c]­pyrazol-7-yloxy)-N-hydroxyacetamide 6n showed noteworthy low nanomolar potency against HepG2, Hela, PC3, and MCF-7 cancer cell lines. In mechanism studies, 6a inhibited tubulin polymerization and disorganized microtubule in A549 cells by binding to tubulin colchicine binding site. 6a arrested A549 cells in G2/M phase that was related to the alterations in the expression of cyclin B1 and p-cdc2. 6a induced A549 cells apoptosis through the activation of caspase-3 and PARP. In addition, 6a inhibited capillary tube formation in a concentration-dependent manner. In nonsmall cell lung cancer xenografts mouse model, 6a suppressed tumor growth by 59.1% at a dose of 50 mg/kg (ip) without obvious toxicity, indicating its in vivo potential as anticancer agent.