Heteroatom-substituted analogues of the active-site directed inhibitor estra-1,3,5(10)-trien-17-one-3-sulphamate inhibit estrone sulphatase by a different mechanism.

Estrogens have a pivotal role in the growth and development of hormone-dependent breast cancers. In postmenopausal women, the hydrolysis of the conjugate estrone sulphate (E1S) to estrone (E1) by the enzyme estrone sulphatase is the major source of breast tumour estrogen. Inhibitors of estrone sulphatase should therefore have considerable therapeutic potential for the treatment of hormone-dependent tumours of the breast, either as the sole agent or in conjunction with aromatase inhibitors. Several inhibitors of estrone sulphatase have now been developed of which estra-1,3,5(10)-trien-17-one-3-sulphamate (EMATE) is the most potent and also inhibits the enzyme in a time- and concentration-dependent manner, showing that it acts as an irreversible inhibitor. Analogues of EMATE in which the 3-O-atom is replaced by other heteroatoms (S and N) were synthesized and tested for inhibition against estrone sulphatase. 4-Methoxyphenylsulphamide (1), 4-chlorothiophenyl-S-(N,N-dimethyl)sulphamate (2), estra-1,3,5(10)-trien-17-one-3-sulphamide (3), estra-1,3,5(10)-trien-17-one-3-S-sulphamate (4) and estra-1,3,5(10)-trien-17-one-3-S-(N,N-dimethyl)sulphamate (5) were found to inhibit estrone sulphatase weakly, but none of these compounds appears to behave as a time-dependent inhibitor. A model of the mechanism of enzyme inhibition by EMATE is proposed and we conclude that the sulphamate bridging oxygen atom of EMATE is essential for active site-directed inhibition of estrone sulphatase.