X-ray crystal structure and mechanism of action of oestrone 3-O-sulphamate, a synthetic active site-directed inhibitor of oestrone sulphatase

Abstract

Oestrone 3-O-sulphamate, wherein a sulphamate moiety is a sulphate group surrogate relative to oestrone sulphate, is the most potent oestrone sulphatase inhibitor developed to date and inhibits oestrone sulphatase in a time- and concentration-dependent manner, showing that it is acting as an active site-directed irreversible inhibitor. It also inhibits dehydroepiandrosterone sulphatase, the enzyme which regulates the synthesis of androstenediol. Oestrone 3-O-sulphamate has also been shown to inhibit these enzymes in-vivo. We report here its crystal structure and the synthesis and inhibitory activites of analogues in which the 3-O atom is replaced by other heteroatoms (N and S). Oestrone 3-N-sulphamate and oestrone 3-S-sulphamate were found to inhibit placental microsome oestrone sulphatase weakly, i.e. 53% and 12%, respectively, at 50 μM (compared with >99% for oestrone 3-O-sulphamate), but none of these compounds appears to behave as a time-dependent inhibitor.