标题: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
作者:Liu, Yan-Na; Wang, Jing-Jing; Ji, Ya-Ting; Zhao, Guo-Dong; Tang, Long-Qian; Zhang, Cheng-Mei; Guo, Xiu-Li; Liu, Zhao-Peng
作者机构:[Liu, Yan-Na; Ji, Ya-Ting; Zhao, Guo-Dong; Tang, Long-Qian; Zhang, Cheng-Mei; Liu, Zhao-Peng] Shandong Univ, Inst Med Chem, Key Lab Chem Biol, Minist 更多
通讯作者:Liu, ZP;Guo, XL
通讯作者地址:[Liu, ZP]Shandong Univ, Inst Med Chem, Key Lab Chem Biol, Minist Educ,Sch Pharmaceut Sci, Jinan 250012, Peoples R China;[Guo, XL]Shandong Univ, Sch Ph 更多
来源:JOURNAL OF MEDICINAL CHEMISTRY
出版年:2016
卷:59
期:11
页码:5341-5355
DOI:10.1021/acs.jmedchem.6b00071
摘要:By targeting a new binding region at the interface between a beta-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.
收录类别:SCOPUS;SCIE
WOS核心被引频次:17
Scopus被引频次:18
资源类型:期刊论文
原文链接:https://www.scopus.com/inward/record.uri?eid=2-s2.0-84974622757&doi=10.1021%2facs.jmedchem.6b00071&partnerID=40&md5=b16080b9799bd4b7a26d32c07bcc2202
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