title: The development of A-ring modified analogues of oestrone-3-O-sulphamate as potent steroid sulphatase inhibitors with reduced oestrogenicity.
abstract: Steroid sulphatases regulate the formation of oestrogenic steroids which can support the growth of endocrine-dependent breast tumours. The development of potent steroid sulphatase inhibitors could therefore have considerable therapeutic potential. Several such inhibitors have now been developed of which the most potent to date is oestrone-3-O-sulphamate (EMATE). Unexpectedly, this inhibitor proved to be a potent oestrogen. In an attempt to reduce the oestrogenicity, whilst retaining the potent sulphatase inhibitory properties associated with this type of molecule, a number of A-ring modified derivatives were designed and synthesized. A-ring modified compounds included the 2-methoxy, 2/4-nitro, 2/4-n-propyl and 2/4-allyl EMATE analogues. The ability of these derivatives to inhibit oestrone sulphatase activity was examined using placental 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 analogues were potent sulphatase inhibitors with 4-nitro EMATE being 5 times more active than EMATE. The 4-nitro, 2-methoxy, 4-n-propyl and 4-allyl derivatives were also tested in vivo for their oestrogenicity and ability to inhibit sulphatase activity. While both 4-nitro and 2-methoxy EMATE were potent inhibitors in vivo, 2-methoxy EMATE had no stimulatory effect on uterine growth in ovariectomized rats. The identification of a potent steroid sulphatase inhibitor lacking any oestrogenicity, such as 2-methoxy EMATE, should be of considerable value in evaluating the potential of steroid sulphatase inhibition for breast cancer therapy.
authors.affiliation: Unit of Metabolic Medicine, Imperial College School of Medicine, St. Mary's Hospital, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Purohit
authors.forename: K A
authors.initials: KA
authors.lastname: Vernon
authors.forename: A E
authors.initials: AE
authors.lastname: Hummelinck
authors.forename: L W
authors.initials: LW
authors.lastname: Woo
authors.forename: H A
authors.initials: HA
authors.lastname: Hejaz
authors.forename: B V
authors.initials: BV
authors.lastname: Potter
authors.forename: M J
authors.initials: MJ
authors.lastname: Reed
mesh_terms: D000818:Animals; D001192:Arylsulfatases / Q000037:antagonists & inhibitors*; D001943:Breast Neoplasms / Q000628:therapy; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D004970:Estrone / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D008861:Microsomes / Q000201:enzymology; D015394:Molecular Structure; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D010920:Placenta / Q000201:enzymology; D051381:Rats; D011919:Rats, Inbred Strains; D043266:Steryl-Sulfatase; D014599:Uterus / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; C088768:estrone-3-O-sulfamate; D004970:Estrone; D001192:Arylsulfatases; D043266:Steryl-Sulfatase; C017296:estrone sulfate