THE DEVELOPMENT OF A-RING MODIFIED ANALOGS OF ESTRONE-3-O-SULFAMATE AS POTENT STEROID SULFATASE INHIBITORS WITH REDUCED ESTROGENICITY

Steroid sulphatases regulate the formation of oestrogenic steroids whi ch can support the growth of endocrine-dependent breast tumours. The d evelopment of potent steroid sulphatase inhibitors could therefore hav e considerable therapeutic potential. Several such inhibitors have now been developed of which the most potent to date is oestrone-3-O-sulph amate (EMATE). Unexpectedly, this inhibitor proved to be a potent oest rogen. In an attempt to reduce the oestrogenicity, whilst retaining th e potent sulphatase inhibitory properties associated with this type of molecule, a number of A-ring modified derivatives were designed and s ynthesized. A-ring modified compounds included the 2-methoxy, 2/4-nitr o, 2/4-n-propyl and 2/4-allyl EMATE analogues. The ability of these de rivatives to inhibit oestrone sulphatase activity was examined using p lacental microsomes. The allyl-substituted EMATE derivatives were more potent inhibitors than the propyl analogues but were all considerably less potent than EMATE. In contrast, the 2-methoxy and 2/4-nitro anal ogues were potent sulphatase inhibitors with 4-nitro EMATE being 5 tim es more active than EMATE. The 4-nitro, 2-methoxy, 4-n-propyl and 4-al lyl derivatives were also tested in vivo for their oestrogenicity and ability to inhibit sulphatase activity. While both 4-nitro and 2-metho xy EMATE were potent inhibitors in vivo, 2-methoxy EMATE had no stimul atory effect on uterine growth in ovariectomized rats. The identificat ion of a potent steroid sulphatase inhibitor lacking any oestrogenicit y, such as 2-methoxy EMATE, should be of considerable value in evaluat ing the potential of steroid sulphatase inhibition for breast cancer t herapy. (C) 1998 Elsevier Science Ltd. All rights reserved.