title: Design, synthesis, biological evaluation and preliminary mechanism study of novel benzothiazole derivatives bearing indole-based moiety as potent antitumor agents.
abstract: Through a structure-based molecular hybridization approach, a series of novel benzothiazole derivatives bearing indole-based moiety were designed, synthesized and screened for in vitro antitumor activity against four cancer cell lines (HT29, H460, A549 and MDA-MB-231). Most of them showed moderate to excellent activity against all the tested cell lines. Among them, compounds 20a-w with substituted benzyl-1H-indole moiety showed better selectivity against HT29 cancer cell line than other compounds. Compound 20d exhibited excellent antitumor activity with IC50 values of 0.024, 0.29, 0.84 and 0.88 μM against HT29, H460, A549 and MDA-MB-231, respectively. Further mechanism studies indicated that the marked pharmacological activity of compound 20d might be ascribed to activation of procaspase-3 (apoptosis-inducing) and cell cycle arrest, which had emerged as a lead for further structural modifications. Furthermore, 3D-QSAR model (training set: q(2) = 0.850, r(2) = 0.987, test set: r(2) = 0.811) was built to provide a comprehensive guide for further structural modification and optimization.
authors: Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, 103 Wenhua Road, Shenhe District, 110016, PR China.
authors: Junjie
authors: J
authors: Ma
authors: Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, 103 Wenhua Road, Shenhe District, 110016, PR China.
authors: Guanglong
authors: G
authors: Bao
authors: Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, 103 Wenhua Road, Shenhe District, 110016, PR China.
authors: Limei
authors: L
authors: Wang
authors: Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, 103 Wenhua Road, Shenhe District, 110016, PR China.
authors: Wanting
authors: W
authors: Li
authors: Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, 103 Wenhua Road, Shenhe District, 110016, PR China.
authors: Boxuan
authors: B
authors: Xu
authors: Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, 103 Wenhua Road, Shenhe District, 110016, PR China.
authors: Baoquan
authors: B
authors: Du
authors: Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, 103 Wenhua Road, Shenhe District, 110016, PR China.
authors: Jie
authors: J
authors: Lv
authors: Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, 103 Wenhua Road, Shenhe District, 110016, PR China. Electronic address: leixinjia@126.com.
authors: Xin
authors: X
authors: Zhai
authors: Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, 103 Wenhua Road, Shenhe District, 110016, PR China. Electronic address: gongpinggp@126.com.
authors: Ping
authors: P
authors: Gong
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D007211:Indoles; C030374:indole; C005465:benzothiazole
keywords: 3D-QSAR; Antitumor activity; Benzothiazole; Indole-based moiety; Synthesis