title: Nonsteroidal compounds designed to mimic potent steroid sulfatase inhibitors.
abstract: Chemical synthesis and enzyme inhibition results are reported for a series of nonsteroidal sulfatase inhibitors, 1-(p-sulfamoyloxyphenyl)-5-(p-t-butylbenzyl)-5-alkanols and the lower active phenolic analogues. These compounds conserve some structural elements from the previously reported potent steroidal inhibitor 3-O-sulfamate-17alpha-(p-t-butylbenzyl)-17beta-hydroxy-estra-1,3,5(10)-triene, while the C18-methyl group and the hydrocarbon backbone represented by the steroid rings B, C, and D were replaced with a free conformational chain. Using estrone sulfate (100 microM) as substrate and homogenate of transfected HEK-293 cells as source of steroid sulfatase activity, the IC(50) values of the best inhibitors, the undecanol derivatives, were 0.4+/-0.1 and >300 nM, respectively, in the sulfamate and phenolic series. Although these sulfamoylated nonsteroidal inhibitors appear a bit less active than their steroidal analogues, they are however more potent than known inhibitors estrone-3-O-sulfamate and p-(O-sulfamoyl)-N-tetradecanoyl tyramine. The optimal side-chain length for the inhibition of steroid sulfatase activity was found to be six carbons, which corresponds to the number of carbons that mimic the B, C and D steroid rings, between C6 and C17. Furthermore, compounds with only the t-butylbenzyl group or the alkyl chain of six carbons are less potent inhibitors compared to the one that include both of these hydrophobic substituents. Such results suggest that compound from this later category better mimic the steroidal inhibitor.
authors.affiliation: Medicinal Chemistry Division, Oncology and Molecular Endocrinology Research Center, Centre Hospitalier Universitaire de Québec (CHUQ), Pavillon CHUL T3-67, 2705 Laurier Boulevard, Sainte-Foy, Qué., Canada G1V 4G2.
authors.forename: Liviu Constantin
authors.initials: LC
authors.lastname: Ciobanu
authors.forename: Van
authors.initials: V
authors.lastname: Luu-The
authors.forename: Donald
authors.initials: D
authors.lastname: Poirier
mesh_terms: D001192:Arylsulfatases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D018716:Molecular Mimicry; D013055:Spectrophotometry, Infrared; D043266:Steryl-Sulfatase; D013451:Sulfonic Acids / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D013451:Sulfonic Acids; C005741:sulfamic acid; D001192:Arylsulfatases; D043266:Steryl-Sulfatase