title: Synthesis and biological activity of 2-aminothiazoles as novel inhibitors of PGE2 production in cells.
abstract: 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 (EC(50)=90 nM) with an IC(50) 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.
authors.affiliation: BIO5 Oro Valley, The University of Arizona, Oro Valley, AZ 85737, United States.
authors.forename: Breland
authors.initials: B
authors.lastname: Smith
authors.forename: Hui-Hua
authors.initials: HH
authors.lastname: Chang
authors.forename: Federico
authors.initials: F
authors.lastname: Medda
authors.forename: Vijay
authors.initials: V
authors.lastname: Gokhale
authors.forename: Justin
authors.initials: J
authors.lastname: Dietrich
authors.forename: Angela
authors.initials: A
authors.lastname: Davis
authors.forename: Emmanuelle J
authors.initials: EJ
authors.lastname: Meuillet
authors.forename: Christopher
authors.initials: C
authors.lastname: Hulme
mesh_terms: D002460:Cell Line; D015232:Dinoprostone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D020128:Inhibitory Concentration 50; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D013844:Thiazoles; C004483:2-aminothiazole; D015232:Dinoprostone