Discovery of a sulfamate-based steroid sulfatase inhibitor with intrinsic selective estrogen receptor modulator properties

• Published in: European journal of medicinal chemistry 2016-08, Vol.119, p.169-182
• Main Authors: Ouellet, Charles, Maltais, René, Ouellet, Étienne, Barbeau, Xavier, Lagüe, Patrick, Poirier, Donald
• Format: Article
• Language: English
• Subjects: Alkaline Phosphatase - metabolism; Amines - chemistry; Cancer; Cell Proliferation - drug effects; Drug Design; Enzyme; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Estrogen; HEK293 Cells; Humans; Inhibitor; Molecular Docking Simulation; Protein Conformation; Selective Estrogen Receptor Modulators - chemistry; Selective Estrogen Receptor Modulators - metabolism; Selective Estrogen Receptor Modulators - pharmacology; SERM; Steryl-Sulfatase - antagonists & inhibitors; Steryl-Sulfatase - chemistry; Steryl-Sulfatase - metabolism; Sulfatase; Sulfonic Acids - chemistry; Sulfonic Acids - metabolism; Sulfonic Acids - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.04.044

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. [Display omitted] •Tetrahydroisoquinoline derivatives were synthesized using an arylsulfamate linker.•Sulfamate tetrahydroisoquinoline derivatives 32–34 inhibit STS (IC50 = 3.9–16.6 nM).•Sulfamate tetrahydroisoquinoline derivatives 32–34 act as SERMs.•Results are supported by molecular docking experiments.•Sulfamate 33 represents a first sulfamate-based inhibitor with intrinsic SERM activity.