Abstract 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/β-catenin signaling pathway that is frequently upregulated in hepatocellular carcinoma (HCC). FH535 was reported as an inhibitor of both β-catenin in the Wnt signaling pathway and the peroxisome proliferator-activated receptor (PPAR). A β-catenin/T-cell factor (TCF)/Lymphoid-enhancer factor (LEF)-dependent assay (i.e., luciferase-based TOPFlash assay) as well as a [3H]-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.
|Number of pages||3|
|Journal||Bioorganic and Medicinal Chemistry Letters|
|State||Published - Aug 17 2015|
Bibliographical noteFunding Information:
C.L. and D.S.W. were supported by R01 CA172379 from the NIH – United States and by the Kentucky Lung Cancer Research Program. B.T.S. and J.J. were supported by R01 DK074816 from the NIH – United States. D.S.W. was supported by the Office of the Dean of the College of Medicine and by NIH Grant number P30 RR020171 from the National Institute of General Medical Sciences to L. Hersh, PI. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the NIGMS.
© 2015 Elsevier Ltd.
- Huh-7 carcinoma cells
- N-Aryl benzenesulfonamides
- Wnt/β-catenin signaling pathway
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry