Recent advances in the development of steroid sulphatase inhibitors

J Steroid Biochem Mol Biol. Apr-Jun 1999;69(1-6):227-38. doi: 10.1016/s0960-0760(99)00039-4.


Inhibition of steroid sulphatase is now an important target for the development of new drugs for the treatment of women with endocrine-dependent breast tumours. The first potent sulphatase inhibitor identified, oestrone-3-O-sulphamate (EMATE) proved. unexpectedly, to be oestrogenic. A number of strategies have therefore been adopted to design and synthesize a non-oestrogenic inhibitor. For this, a number of modifications have been made to the A and D rings of the oestrone nucleus. 2 Methoxyoestrone-3-O-sulphamate, while having similar in vitro and in vivo sulphatase inhibitory potency to that of EMATE, was devoid of oestrogenic activity when tested at 2 mg/kg in an ovariectomised rat uterine weight gain assay. 17-Deoxyoestrone-3-O-sulphamate was also a potent steroid sulphatase inhibitor and while it was devoid of oestrogenic activity when tested at 0.1 mg/kg, did stimulate uterine growth at 1.0 mg/kg. As an alternative approach to the use of steroid-based inhibitors a number of single ring, bicyclic non-fused ring, and two fused ring sulphamate analogues were designed, synthesized and tested for their ability to inhibit steroid sulphatase activity. In general, although the single ring and bicyclic non-fused ring sulphamate analogues could inhibit sulphatase activity, they were considerably less potent than EMATE. The mono- and bis-sulphamate derivatives of 5,7-dihydroxyisoflavone were relatively potent, inhibiting in vivo steroid sulphatase activity by 62 and 81% respectively at a single oral dose of 10 mg/kg. A study of the structure-activity relationship of a series of coumarin-based sulphamates has led to the development of a number of potent non-steroidal inhibitors, one of which has a similar potency to that of EMATE. The identification of potent steroid- and non-steroid-based sulphatase inhibitors will enable the therapeutic value of this therapy to be examined in the near future.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arylsulfatases / antagonists & inhibitors*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Estrogen Antagonists / pharmacology
  • Female
  • Magnetic Resonance Spectroscopy
  • Molecular Structure
  • Progestins / pharmacology
  • Rats
  • Rats, Wistar
  • Spectrometry, Mass, Fast Atom Bombardment
  • Steryl-Sulfatase
  • Tumor Cells, Cultured


  • Enzyme Inhibitors
  • Estrogen Antagonists
  • Progestins
  • Arylsulfatases
  • Steryl-Sulfatase