HETEROATOM-SUBSTITUTED ANALOGS OF THE ACTIVE-SITE-DIRECTED INHIBITOR ESTRA-1,3,5(10)-TRIEN-17-ONE-3-SULFAMATE INHIBIT ESTRONE SULFATASE 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 (E(1)S) to estrone (E(1)) by the enzyme estrone sulphatase is the major source of breast tumour estrogen. Inh ibitors of estrone sulphatase should therefore have considerable thera peutic potential for the treatment of hormone-dependent tumours of the breast, either as the sole agent or in conjunction with aromatase inh ibitors. Several inhibitors of estrone sulphatase have now been develo ped 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. A nalogues of EMATE in which the 3-O-atom is replaced by other heteroato ms (S and N) were synthesized and tested for inhibition against estron e 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 ,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 inhibitio n by EMATE is proposed and we conclude that the sulphamate bridging ox ygen atom of EMATE is essential for active site-directed inhibition of estrone sulphatase. (C) 1996 Elsevier Science Ltd.