title: Synthesis and biological evaluation of benzothiazole derivatives bearing the ortho-hydroxy-N-acylhydrazone moiety as potent antitumor agents.
abstract: A novel series of benzothiazole derivatives bearing the ortho-hydroxy-N-acylhydrazone moiety were designed, synthesized, and evaluated for their procaspase-3 kinase activation activities and antiproliferative activities against five cancer cell lines (NCI-H226, SK-N-SH, HT29, MKN-45, and MDA-MB-231). Most target compounds showed moderate to excellent cytotoxic activity against all five tested cancer lines. The most promising compound 18e (procaspase-3 EC50  = 0.31 µM) with IC50 values ranging from 0.24 to 0.92µM against all tested cell lines was 4.24-12.2 times more active than PAC-1 (procaspase-3 EC50  = 0.41 µM). Structure-activity relationship studies indicated that the phenyl group on the 2-hydroxyphenyl ring (moiety A) was critical for pharmacological activity in vitro. In addition, introduction of a benzyloxyl group on moiety A and a mono-electron-withdrawing group at the 4-position of the benzyloxyl group were more favorable for antitumor activity. Moreover, reduction of the electron density in the phenyl ring of the benzyloxy group led to a dramatic decrease in the procaspase-3 kinase activation activity.
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenhe District, Shenyang, P. R. China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Ma
authors.forename: Guangyan
authors.initials: G
authors.lastname: Zhang
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Han
authors.forename: Guanglong
authors.initials: G
authors.lastname: Bao
authors.forename: Lihui
authors.initials: L
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Zhai
authors.forename: Ping
authors.initials: P
authors.lastname: Gong
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004789:Enzyme Activation; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D006835:Hydrazones; D053148:Caspase 3
keywords: Antitumor; Benzothiazole; Procaspase-3; ortho-Hydroxy-N-acylhydrazone moiety