Synthesis and biological activity of 2-aminothiazoles as novel inhibitors of PGE2 production in cells

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:22

Article

Smith, Breland^1,2  Chang, Hui-Hua^3,4  Medda, Federico¹  Gokhale, Vijay⁵  Dietrich, Justin¹  Davis, Angela⁵  Meuillet, Emmanuelle J.^3,4  Hulme, Christopher^1,5 

[1] Univ Arizona, Oro Valley BIO5, Oro Valley, AZ 85737 USA

[2] Univ Arizona, Dept Chem & Biochem, Tucson, AZ 85721 USA

[3] Univ Arizona, Dept Nutr Sci, Arizona Canc Ctr, Tucson, AZ 85724 USA

[4] Univ Arizona, Dept Mol & Cellular Biol, Arizona Canc Ctr, Tucson, AZ 85724 USA

[5] Univ Arizona, Dept Pharmacol & Toxicol, Coll Pharm, Tucson, AZ 85721 USA

关键词: 2-Aminothiazoles;    PGE(2);    Colon cancer;    COX-2;   

DOI  :  10.1016/j.bmcl.2012.03.013

来源: Elsevier

【 摘 要 】

This Letter presents the synthesis and biological evaluation of a collection of 2-aminothiazoles as a novel class of compounds with the capability to reduce the production of PGE(2) in HCA-7 human adenocarcinoma cells. A total of 36 analogs were synthesized and assayed for PGE(2) reduction, and those with potent cellular activity were counter screened for inhibitory activity against COX-2 in a cell free assay. In general, analogs bearing a 4-phenoxyphenyl substituent in the R-2 position were highly active in cells while maintaining negligible COX-2 inhibition. Specifically, compound 5l (R-1 = Me, R-2 = 4-OPh-Ph, R-3 = CH(OH)Me) exhibited the most potent cellular PGE(2) reducing activity of the entire series (EC50 = 90 nM) with an IC50 value for COX-2 inhibition of >5 mu M in vitro. Furthermore, the anti-tumor activity of analog 1a was analyzed in xenograft mouse models exhibiting promising anti-cancer activity. (C) 2012 Elsevier Ltd. All rights reserved.

【 授权许可】

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