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

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.