Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 22, Issue 10, Pages 3567-3570Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2012.03.013
Keywords
2-Aminothiazoles; PGE(2); Colon cancer; COX-2
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Funding
- NIH (BCP) [5T32GM008804-09]
- University of Arizona College of Pharmacy
- [SR01CA138702]
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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.
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