6-(2-adamantan-2-ylidene-hydroxybenzoxazole)-O-sulfamate: a potent non-steroidal irreversible inhibitor of human steroid sulfatase

Bioorg Med Chem Lett. 2003 Dec 15;13(24):4313-6. doi: 10.1016/j.bmcl.2003.09.050.

Abstract

We report the synthesis and results from the in vitro evaluation of 6-(adamantan-2-ylidene-hydroxybenzoxazole)-O-sulfamate 1 as an irreversible inhibitor of human steroid sulfatase (STS). Highly straightforward, condensation of 2-methyl-6-hydroxybenzoxazole with 2-adamantanone, subsequent elimination of water and sulfamoylation provide the title compound in 45% overall yield from the inexpensive 2,4-dihydroxyacetophenone. 1 was found to be a potent irreversible inhibitor of purified human steroid sulfatase (STS) and specific for this enzyme relative to human arylsulfatases A and B. In cellular assays with human keratinocytes, sebocytes and fibroblasts, 1 blocked STS activity with IC(50) values in the range of 0.15-0.8 nM, and in MCF-7 breast cancer cells with IC(50)=2.3 nM, while it did not bind to estrogen receptors alpha and beta. Thus, 1 is a candidate for further investigation of its potential as a drug to be used in androgen- and estrogen-dependent diseases.

MeSH terms

  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Guanine / analogs & derivatives*
  • Guanine / chemical synthesis*
  • Guanine / chemistry
  • Guanine / pharmacology*
  • Humans
  • Kinetics
  • Models, Molecular
  • Molecular Conformation
  • Steryl-Sulfatase / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • 6-(2-acetylvinylthio)guanine
  • Enzyme Inhibitors
  • Guanine
  • Steryl-Sulfatase