title: Design, synthesis, and structure-activity relationships of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety as potent antitumor agents.
abstract: A series of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety were designed and synthesized and their cytotoxic activities against five cancer cell lines (NCI-H226, SK-N-SH, HT29, MKN45, and MDA-MB-231) were screened in vitro. Most of them showed moderate to excellent activity against all the tested cell lines. Among them, compounds 15g (procaspase-3 EC50 = 1.42 μM) and 16b (procaspase-3 EC50 = 0.25 μM) exhibited excellent antitumor activity with IC50 values ranging from 0.14 μM to 0.98 μM against all cancer cell lines, which were 1.8-8.7 times more active than the first procaspase activating compound (PAC-1) (procaspase-3 EC50 = 4.08 μM). The structure-activity relationship (SAR) analyses indicated that the introduction of a lipophilic group (a benzyloxy or heteroaryloxy group) at the 4-position of the 2-hydroxy phenyl ring was beneficial to antitumor activity, and the presence of substituents containing nitrogen that are positively charged at physiological pH could also improve antitumor activity. It was also confirmed that the steric effect of the 4-position substituent of the benzyloxy group had a significant influence on cytotoxic activity.
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University) Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning 110016, PR China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Ma
authors.affiliation: Qilu Pharmaceutical Research Institute, Qilu Pharmaceutical Co., Ltd., Ji'nan 250100, PR China.
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University) Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning 110016, PR China.
authors.forename: Kuan
authors.initials: K
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University College of Life Science and Biopharmaceutical, Shenyang 110016, PR China.
authors.forename: Lihui
authors.initials: L
authors.lastname: Wang
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University) Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning 110016, PR China.
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Han
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University) Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning 110016, PR China.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University) Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning 110016, PR China. Electronic address: gongpinggp@126.com.
authors.forename: Ping
authors.initials: P
authors.lastname: 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; D019073:HT29 Cells; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D006834:Hydrazines; C005465:benzothiazole
keywords: Antitumor; Benzothiazole; Ortho-hydroxy N-Carbamoylhydrazone moiety; Procaspase-3