title: Discovery of a sulfamate-based steroid sulfatase inhibitor with intrinsic selective estrogen receptor modulator properties.
abstract: Steroid sulfatase (STS), the enzyme which converts inactive sulfated steroid precursors into active hormones, is a promising therapeutic target for the treatment of estrogen-sensitive breast cancer. We report herein the synthesis and in vitro study of dual-action STS inhibitors with selective estrogen-receptor modulator (SERM) effects. A library of tetrahydroisoquinoline-N-substituted derivatives (phenolic compounds) was synthesized by solid-phase chemistry and tested on estrogen-sensitive breast cancer T-47D cells. Three phenolic compounds devoid of estrogenic activity and toxicity emerged from this screening. Their sulfamate analogs were then synthesized, tested in STS-transfected HEK-293 cells, and found to be potent inhibitors of the enzyme (IC50 of 3.9, 8.9, and 16.6 nM). When tested in T-47D cells they showed no estrogenic activity and produced a moderate antiestrogenic activity. The compounds were further tested on osteoblast-like Saos-2 cells and found to significantly stimulate their proliferation as well as their alkaline phosphatase activity, thus suggesting a SERM activity. These results are supported by molecular docking experiments.
authors.affiliation: Laboratory of Medicinal Chemistry, CHU de Québec - Research Center (CHUL, T4), 2705 Laurier Boulevard, Québec, QC, G1V 4G2, Canada.
authors.forename: Charles
authors.initials: C
authors.lastname: Ouellet
authors.affiliation: Laboratory of Medicinal Chemistry, CHU de Québec - Research Center (CHUL, T4), 2705 Laurier Boulevard, Québec, QC, G1V 4G2, Canada.
authors.forename: René
authors.initials: R
authors.lastname: Maltais
authors.affiliation: Laboratory of Medicinal Chemistry, CHU de Québec - Research Center (CHUL, T4), 2705 Laurier Boulevard, Québec, QC, G1V 4G2, Canada.
authors.forename: Étienne
authors.initials: É
authors.lastname: Ouellet
authors.affiliation: Département de chimie, Institut de biologie intégrative et des systèmes (IBIS), Centre de recherche sur la fonction, la structure et l'ingénierie des protéines (PROTEO), Université Laval, Québec City, QC, Canada.
authors.forename: Xavier
authors.initials: X
authors.lastname: Barbeau
authors.affiliation: Département de biochimie microbiologie et bio-informatique, Institut de biologie intégrative et des systèmes (IBIS), Centre de recherche sur la fonction, la structure et l'ingénierie des protéines (PROTEO), Université Laval, Québec City, QC, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lagüe
authors.affiliation: Laboratory of Medicinal Chemistry, CHU de Québec - Research Center (CHUL, T4), 2705 Laurier Boulevard, Québec, QC, G1V 4G2, Canada; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada. Electronic address: donald.poirier@crchul.ulaval.ca.
authors.forename: Donald
authors.initials: D
authors.lastname: Poirier
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000588:Amines / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D020845:Selective Estrogen Receptor Modulators / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013451:Sulfonic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000588:Amines; D004791:Enzyme Inhibitors; D020845:Selective Estrogen Receptor Modulators; D013451:Sulfonic Acids; C005741:sulfamic acid; D000469:Alkaline Phosphatase; D043266:Steryl-Sulfatase
keywords: Cancer; Enzyme; Estrogen; Inhibitor; SERM; Sulfatase