title: 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.
abstract: 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.
authors.affiliation: Institute of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences and ‡Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University , Jinan 250012, P. R. China.
authors.forename: Yan-Na
authors.initials: YN
authors.lastname: Liu
authors.affiliation: Institute of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences and ‡Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University , Jinan 250012, P. R. China.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: Institute of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences and ‡Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University , Jinan 250012, P. R. China.
authors.forename: Ya-Ting
authors.initials: YT
authors.lastname: Ji
authors.affiliation: Institute of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences and ‡Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University , Jinan 250012, P. R. China.
authors.forename: Guo-Dong
authors.initials: GD
authors.lastname: Zhao
authors.affiliation: Institute of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences and ‡Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University , Jinan 250012, P. R. China.
authors.forename: Long-Qian
authors.initials: LQ
authors.lastname: Tang
authors.affiliation: Institute of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences and ‡Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University , Jinan 250012, P. R. China.
authors.forename: Cheng-Mei
authors.initials: CM
authors.lastname: Zhang
authors.affiliation: Institute of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences and ‡Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University , Jinan 250012, P. R. China.
authors.forename: Xiu-Li
authors.initials: XL
authors.lastname: Guo
authors.affiliation: Institute of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences and ‡Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University , Jinan 250012, P. R. China.
authors.forename: Zhao-Peng
authors.initials: ZP
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000737:chemistry / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000619632:1-methyl-1,4-dihydroindeno(1,2-c)pyrazole; D000970:Antineoplastic Agents; D011720:Pyrazoles; D014404:Tubulin; D050257:Tubulin Modulators; D003078:Colchicine