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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.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Ouellet C,Maltais R,Ouellet É,Barbeau X,Lagüe P,Poirier D

doi

10.1016/j.ejmech.2016.04.044

subject

Has Abstract

pub_date

2016-08-25 00:00:00

pages

169-82

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(16)30337-3

journal_volume

119

pub_type

杂志文章

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