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

Breland Smith; Hui Hua Chang; Federico Medda; Vijay Gokhale; Justin Dietrich; Angela Davis; Emmanuelle J. Meuillet; Christopher Hulme

doi:10.1016/j.bmcl.2012.03.013

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

Breland Smith, Hui Hua Chang, Federico Medda, Vijay Gokhale, Justin Dietrich, Angela Davis, Emmanuelle J. Meuillet, Christopher Hulme

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

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.

Original language	English (US)
Pages (from-to)	3567-3570
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	22
Issue number	10
DOIs	https://doi.org/10.1016/j.bmcl.2012.03.013
State	Published - May 15 2012

Keywords

2-Aminothiazoles
COX-2
Colon cancer
PGE

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

Access to Document

10.1016/j.bmcl.2012.03.013

Cite this

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title = "Synthesis and biological activity of 2-aminothiazoles as novel inhibitors of PGE 2 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.",

keywords = "2-Aminothiazoles, COX-2, Colon cancer, PGE",

author = "Breland Smith and Chang, {Hui Hua} and Federico Medda and Vijay Gokhale and Justin Dietrich and Angela Davis and Meuillet, {Emmanuelle J.} and Christopher Hulme",

note = "Funding Information: The authors would like to thank financial support provided by an NIH training Grant research fellowship (BCP Fellowship, Grant # 5T32GM008804-09 ), the University of Arizona College of Pharmacy for start-up funds and SR01CA138702 . Finally, the authors graciously acknowledge Kristen Keck for selected compound purification, Alex Laetsch for compound management and Nicole Schechter for group coordination.",

year = "2012",

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doi = "10.1016/j.bmcl.2012.03.013",

language = "English (US)",

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journal = "Bioorganic and Medicinal Chemistry Letters",

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T1 - Synthesis and biological activity of 2-aminothiazoles as novel inhibitors of PGE 2 production in cells

AU - Smith, Breland

AU - Chang, Hui Hua

AU - Medda, Federico

AU - Gokhale, Vijay

AU - Dietrich, Justin

AU - Davis, Angela

AU - Meuillet, Emmanuelle J.

AU - Hulme, Christopher

N1 - Funding Information: The authors would like to thank financial support provided by an NIH training Grant research fellowship (BCP Fellowship, Grant # 5T32GM008804-09 ), the University of Arizona College of Pharmacy for start-up funds and SR01CA138702 . Finally, the authors graciously acknowledge Kristen Keck for selected compound purification, Alex Laetsch for compound management and Nicole Schechter for group coordination.

PY - 2012/5/15

Y1 - 2012/5/15

N2 - 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.

AB - 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.

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