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

作者：Ouellet Charles; Maltais Rene; Ouellet Etienne; Barbeau Xavier; Lague Patrick; Poirier Donald^*

来源：European Journal of Medicinal Chemistry, 2016, 119: 169-182.

DOI：10.1016/j.ejmech.2016.04.044

• Sulfatase
• Enzyme
• Inhibitor
• Estrogen
• Cancer
• SERM

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.

• 出版日期2016-8-25