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

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• 作者：Breland Smith^a ; ^b ; Hui-Hua Chang^c ; Federico Medda^a ; Vijay Gokhale^d ; Justin Dietrich^a ; Angela Davis^d ; Emmanuelle J. Meuillet^c ; Christopher Hulme^a ; ^d ; ^{hulme@pharmacy.arizona.edu}
• 关键词：2-Aminothiazoles ; PGE2 ; Colon cancer ; COX-2
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 May, 2012
• 卷：22
• 期：10
• 页码：3567-3570
• 文件大小：502 K

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 PGE₂ in HCA-7 human adenocarcinoma cells. A total of 36 analogs were synthesized and assayed for PGE₂ 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 R² position were highly active in cells while maintaining negligible COX-2 inhibition. Specifically, compound 5l (R¹ = Me, R² = 4-OPh-Ph, R³ = CH(OH)Me) exhibited the most potent cellular PGE₂ reducing activity of the entire series (EC₅₀ = 90 nM) with an IC₅₀ value for COX-2 inhibition of >5 渭M in vitro. Furthermore, the anti-tumor activity of analog 1a was analyzed in xenograft mouse models exhibiting promising anti-cancer activity.