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.
Schreiner
Erwin P
EP
Novartis Forschungsinstitut, Brunner Strasse 59, A-1235 Vienna, Austria. erwin.schreiner@pharma.novartis.com
Wolff
Barbara
B
Winiski
Anthony P
AP
Billich
Andreas
A
D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C451721:6-(2-acetylvinylthio)guanine; D004791:Enzyme Inhibitors; D006147:Guanine; D043266:Steryl-Sulfatase