N-Aryl benzenesulfonamide inhibitors of [3H]-thymidine incorporation and β-catenin signaling in human hepatocyte-derived Huh-7 carcinoma cells

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:25

Article

Kril, Liliia M.^1,2  Vilchez, Valery³  Jiang, Jieyun^4,5  Turcios, Lilia³  Chen, Changguo³  Sviripa, Vitaliy M.^1,2  Zhang, Wen^1,5  Liu, Chunming^1,5  Spear, Brett^4,5  Watt, David S.^1,2,5  Gedaly, Roberto^3,5 

[1] Univ Kentucky, Coll Med, Dept Mol & Cellular Biochem, Lexington, KY 40536 USA

[2] Univ Kentucky, Coll Pharm, Ctr Pharmaceut Res & Innovat, Lexington, KY 40536 USA

[3] Univ Kentucky, Dept Surg, Coll Med, Lexington, KY 40536 USA

[4] Univ Kentucky, Dept Microbiol Immunol & Mol Genet, Lexington, KY 40536 USA

[5] Univ Kentucky, Lucille Parker Markey Canc Ctr, Lexington, KY 40536 USA

关键词: FH535;    Inhibitor;    beta-Catenin;    Wnt/beta-catenin signaling pathway;    N-Aryl benzenesulfonamides;    Huh-7 carcinoma cells;   

DOI  :  10.1016/j.bmcl.2015.07.040

来源: Elsevier

【 摘 要 】

Structure-activity relationships (SAR) in 2,5-dichloro-N-(2-methyl-4-nitrophenyl) benzenesulfonamide (FH535) were examined as part of a program to identify agents that inhibit the Wnt/beta-catenin signaling pathway that is frequently upregulated in hepatocellular carcinoma (HCC). FH535 was reported as an inhibitor of both beta-catenin in the Wnt signaling pathway and the peroxisome proliferator-activated receptor (PPAR). A beta-catenin/T-cell factor (TCF)/Lymphoid-enhancer factor (LEF)-dependent assay (i.e., luciferase-based TOPFlash assay) as well as a [H-3]-thymidine incorporation assay were used to explore SAR modifications of FH535. Although replacing the 2,5-dichlorophenylsulfonyl substituent in FH535 with a 2,6-dihalogenation pattern generally produced more biologically active analogs than FH535, other SAR modifications led only to FH535 analogs with comparable or slightly improved activity in these two assays. The absence of a clear SAR pattern in activity suggested a multiplicity of target effectors for N-aryl benzenesulfonamides. (C) 2015 Elsevier Ltd. All rights reserved.

【 授权许可】

Free