Synthesis and biological activity of aminophthalazines and aminopyridazines as novel inhibitors of PGE2 production in cells

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:23

Article

Medda, Federico^1,4  Sells, Earlphia^2,3  Chang, Hui-Hua^2,3  Dietrich, Justin^1,4  Chappeta, Shashi⁴  Smith, Breland¹  Gokhale, Vijay¹  Meuillet, Emmanuelle J.^2,3  Hulme, Christopher^1,4,5 

[1] Univ Arizona, Oro Valley BIO5, Oro Valley, AZ 85737 USA

[2] Univ Arizona, Dept Nutr Sci, Tucson, AZ 85724 USA

[3] Univ Arizona, Dept Mol & Cellular Biol, Tucson, AZ 85724 USA

[4] Univ Arizona, Dept Pharmacol & Toxicol, Coll Pharm, Tucson, AZ 85721 USA

[5] Univ Arizona, Dept Chem & Biochem, Tucson, AZ 85721 USA

关键词: Aminophthalazines;    PGE(2);    COX-2;    Cancer;   

DOI  :  10.1016/j.bmcl.2012.11.030

来源: Elsevier

【 摘 要 】

This Letter reports the synthesis and biological evaluation of a collection of aminophthalazines as a novel class of compounds capable of reducing production of PGE(2) in HCA-7 human adenocarcinoma cells. A total of 28 analogs were synthesized, assayed for PGE2 reduction, and selected active compounds were evaluated for inhibitory activity against COX-2 in a cell free assay. Compound 2xxiv (R-1 = H, R-2 = p-CH3O) exhibited the most potent activity in cells (EC50 = 0.02 mu M) and minimal inhibition of COX-2 activity (3% at 5 mu M). Furthermore, the anti-tumor activity of analog 2vii was analyzed in xenograft mouse models exhibiting good anti-cancer activity. (C) 2012 Elsevier Ltd. All rights reserved.

【 授权许可】

Free