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

Liliia M. Kril; Valery Vilchez; Jieyun Jiang; Lilia Turcios; Changguo Chen; Vitaliy M. Sviripa; Wen Zhang; Chunming Liu; Brett Spear; David S. Watt; Roberto Gedaly

doi:10.1016/j.bmcl.2015.07.040

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

Liliia M. Kril, Valery Vilchez, Jieyun Jiang, Lilia Turcios, Changguo Chen, Vitaliy M. Sviripa, Wen Zhang, Chunming Liu, Brett Spear, David S. Watt, Roberto Gedaly

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

11 Scopus citations

Abstract

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.

Original language	English
Article number	22929
Pages (from-to)	3897-3899
Number of pages	3
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	25
Issue number	18
DOIs	https://doi.org/10.1016/j.bmcl.2015.07.040
State	Published - Aug 17 2015

Bibliographical note

Publisher Copyright:
© 2015 Elsevier Ltd.

Funding

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.

Funders	Funder number
Kentucky Lung Cancer Research Program	R01 DK074816, P30 RR020171
National Institutes of Health (NIH)
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences
National Institute of Diabetes and Digestive and Kidney Diseases	R01DK074816

Keywords

FH535
Huh-7 carcinoma cells
Inhibitor
N-Aryl benzenesulfonamides
Wnt/β-catenin signaling pathway
β-Catenin

ASJC Scopus subject areas

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

Access to Document

10.1016/j.bmcl.2015.07.040

Cite this

Kril, L. M., Vilchez, V., Jiang, J., Turcios, L., Chen, C., Sviripa, V. M., Zhang, W., Liu, C., Spear, B., Watt, D. S., & Gedaly, R. (2015). N-Aryl benzenesulfonamide inhibitors of [³H]-thymidine incorporation and β-catenin signaling in human hepatocyte-derived Huh-7 carcinoma cells. Bioorganic and Medicinal Chemistry Letters, 25(18), 3897-3899. Article 22929. https://doi.org/10.1016/j.bmcl.2015.07.040

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

abstract = "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.",

keywords = "FH535, Huh-7 carcinoma cells, Inhibitor, N-Aryl benzenesulfonamides, Wnt/β-catenin signaling pathway, β-Catenin",

author = "Kril, \{Liliia M.\} and Valery Vilchez and Jieyun Jiang and Lilia Turcios and Changguo Chen and Sviripa, \{Vitaliy M.\} and Wen Zhang and Chunming Liu and Brett Spear and Watt, \{David S.\} and Roberto Gedaly",

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Ltd.",

year = "2015",

month = aug,

day = "17",

doi = "10.1016/j.bmcl.2015.07.040",

language = "English",

volume = "25",

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Kril, LM, Vilchez, V, Jiang, J, Turcios, L, Chen, C, Sviripa, VM, Zhang, W, Liu, C , Spear, B, Watt, DS & Gedaly, R 2015, 'N-Aryl benzenesulfonamide inhibitors of [³H]-thymidine incorporation and β-catenin signaling in human hepatocyte-derived Huh-7 carcinoma cells', Bioorganic and Medicinal Chemistry Letters, vol. 25, no. 18, 22929, pp. 3897-3899. https://doi.org/10.1016/j.bmcl.2015.07.040

TY - JOUR

T1 - N-Aryl benzenesulfonamide inhibitors of [3H]-thymidine incorporation and β-catenin signaling in human hepatocyte-derived Huh-7 carcinoma cells

AU - Kril, Liliia M.

AU - Vilchez, Valery

AU - Jiang, Jieyun

AU - Turcios, Lilia

AU - Chen, Changguo

AU - Sviripa, Vitaliy M.

AU - Zhang, Wen

AU - Liu, Chunming

AU - Spear, Brett

AU - Watt, David S.

AU - Gedaly, Roberto

PY - 2015/8/17

Y1 - 2015/8/17

N2 - 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.

AB - 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.

KW - FH535

KW - Huh-7 carcinoma cells

KW - Inhibitor

KW - N-Aryl benzenesulfonamides

KW - Wnt/β-catenin signaling pathway

KW - β-Catenin

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