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

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 μM in vitro. Furthermore, the anti-tumor activity of analog 1a was analyzed in xenograft mouse models exhibiting promising anti-cancer activity.

Graphical abstractThis 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 colon cancer cells. A total of 36 analogs were tested and active compounds were identified. Furthermore, the anti-tumor activity of analog 1a was analyzed in xenograft mouse models exhibiting promising anti-cancer activity.Figure optionsDownload full-size imageDownload as PowerPoint slide