title: N-Aryl benzenesulfonamide inhibitors of [3H]-thymidine incorporation and β-catenin signaling in human hepatocyte-derived Huh-7 carcinoma cells.
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 [(3)H]-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.
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, United States; Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, United States.
authors.forename: Liliia M
authors.initials: LM
authors.lastname: Kril
authors.affiliation: Department of Surgery, College of Medicine, University of Kentucky, Lexington, KY 40536-0596, United States.
authors.forename: Valery
authors.initials: V
authors.lastname: Vilchez
authors.affiliation: Department of Microbiology, Immunology & Molecular Genetics, University of Kentucky, Lexington, KY 40536-0093, United States; Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40536-0093, United States.
authors.forename: Jieyun
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Surgery, College of Medicine, University of Kentucky, Lexington, KY 40536-0596, United States.
authors.forename: Lilia
authors.initials: L
authors.lastname: Turcios
authors.affiliation: Department of Surgery, College of Medicine, University of Kentucky, Lexington, KY 40536-0596, United States.
authors.forename: Changguo
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, United States; Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, United States.
authors.forename: Vitaliy M
authors.initials: VM
authors.lastname: Sviripa
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, United States; Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40536-0093, United States.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, United States; Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40536-0093, United States.
authors.forename: Chunming
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Microbiology, Immunology & Molecular Genetics, University of Kentucky, Lexington, KY 40536-0093, United States; Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40536-0093, United States.
authors.forename: Brett
authors.initials: B
authors.lastname: Spear
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, United States; Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, United States; Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40536-0093, United States. Electronic address: dwatt@uky.edu.
authors.forename: David S
authors.initials: DS
authors.lastname: Watt
authors.affiliation: Department of Surgery, College of Medicine, University of Kentucky, Lexington, KY 40536-0596, United States; Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40536-0093, United States. Electronic address: rgeda2@uky.edu.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gedaly
mesh_terms: D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism*; D000096926:Benzenesulfonamides
chemical_list: D013449:Sulfonamides; D013936:Thymidine; D051176:beta Catenin; D000096926:Benzenesulfonamides
keywords: FH535; Huh-7 carcinoma cells; Inhibitor; N-Aryl benzenesulfonamides; Wnt/β-catenin signaling pathway; β-Catenin