The difluoromethylene group as a replacement for the labile oxygen in steroid sulfates: a new approach to steroid sulfatase inhibitors.
Several estrone sulfate and estradiol sulfate analogues, in which the sulfate group was replaced with an alpha,alpha-difluoromethylenesulfonate group or an alpha,alpha-difluoromethylenetetrazole group, were examined as inhibitors of steroid sulfatase (STS). These compounds were 4.5-10.5 times more potent than their non-fluorinated analogues. Moreover, the presence of the fluorines changed the mode of inhibition from mixed to competitive. The inhibitor bearing the alpha,alpha-difluoromethylenetetrazole group exhibited an affinity for STS approaching that of the natural STS substrate, estrone sulfate. Possible reasons for the enhanced affinity of the fluorinated compounds compared to their non-fluorinated counterparts are discussed.
Lapierre
Jennifer
J
Department of Chemistry, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1.
Ahmed
Vanessa
V
Chen
Mei-Jin
MJ
Ispahany
Mehdi
M
Guillemette
J Guy
JG
Taylor
Scott D
SD
D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry*; D004970:Estrone / Q000031:analogs & derivatives* / Q000737:chemistry*; D006801:Humans; D010100:Oxygen / Q000737:chemistry*; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; C031555:estradiol sulfate; D004970:Estrone; D004958:Estradiol; D043266:Steryl-Sulfatase; C017296:estrone sulfate; D010100:Oxygen