2-Difluoromethyloestrone 3- O-sulphamate, a highly potent steroid sulphatase inhibitor

Abstract

Steroid sulphatase is a target enzyme of growing therapeutic importance. The synthesis and in vitro biological evaluation of three novel 2-substituted analogues of oestrone 3- O-sulphamate (EMATE), an established steroid sulphatase inhibitor, are described. One inhibitor, 2-difluoromethyloestrone 3- O-sulphamate ( 6), was found to have an IC 50 of 100 pM and be some 90-fold more potent than EMATE in inhibiting steroid sulphatase activity in a placental microsomal preparation, rendering this agent the most potent steroidal STS inhibitor in vitro reported to date. Lowering of the p K a value of the leaving parent steroid phenol by the 2-difluoromethyl group during irreversible enzyme sulphamoylation most likely facilitates the potent inactivation of steroid sulphatase by ( 6). However, our preliminary molecular docking studies using the X-ray crystal structure of steroid sulphatase suggest that F⋯⋯H interactions between the 2-difluoromethyl group of ( 6) and hydrogen bond donor residues lining the catalytic site of STS might also contribute to the high potency observed for ( 6).