title: 17Alpha-alkan (or alkyn) amide derivatives of estradiol as inhibitors of steroid-sulfatase activity.
abstract: To develop inhibitors of steroid sulfatase without residual estrogenic activity, we have designed a series of estradiol (E2) derivatives bearing an alkan (or alkyn) amide side chain at position 17alpha. A hydrophobic alkyl group was selected from our previous study where 17alpha-octyl-E2 was found to inhibit strongly the steroid-sulfatase activity. Furthermore, it is known that an alkylamide side chain blocks the estrogen-receptor activation. Starting from ethynylestradiol, the chemical synthesis of target compounds was short and efficient with overall yields of 22-42% (3 or 4 steps). Among these compounds, N-octyl,N-methyl-3-(3',17'beta-dihydroxy-1',3',5'(10')-estratrien- 17'alpha-yl)-propanamide (15) was the most potent inhibitor, with an IC50 value of 0.08 microM for the transformation of estrone sulfate (E1S) to estrone (E1) by homogenated JEG-3 cells. N-butyl, N-hexyl, and N,N-dioctyl propanamide derivatives of E2 (IC50 values of 6.4, 2.8, and >20 microM, respectively) were less potent inhibitors than N-octyl analog 15. Furthermore, the unsaturated propynamide analog of 15 gave lower inhibition (four times) than the saturated compound. Compound 15 is also about 100-fold more effective in interacting with the enzyme than substrate E1S itself. The ability of target compounds to bind the estrogen receptor, to stimulate the proliferation of estrogen-sensitive ZR-75-1 cells, or to inhibit the E2-stimulation of ZR-75-1 cells was also evaluated. Although a mixed estrogenic/anti-estrogenic activity was obtained for tested compounds at 1 microM, no estrogenic activity was observed at 0.03 microM for 15. In conclusion, a promising inhibitor of steroid-sulfatase activity was obtained by introducing a hydrophobic octyl group in a 17alpha-propanamide side chain of E2, but further structure-activity relationships (SAR) studies are necessary to minimize the residual estrogenic activity.
authors.affiliation: Medicinal Chemistry Division, Laval University Medical Research Center, Centre Hospitalier Universitaire de Québec et Université Laval, Sainte-Foy, Canada.
authors.forename: R P
authors.initials: RP
authors.lastname: Boivin
authors.forename: F
authors.initials: F
authors.lastname: Labrie
authors.forename: D
authors.initials: D
authors.lastname: Poirier
mesh_terms: D000577:Amides / Q000737:chemistry; D001192:Arylsulfatases / Q000037:antagonists & inhibitors*; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000378:metabolism; D043266:Steryl-Sulfatase; D014407:Tumor Cells, Cultured
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D011960:Receptors, Estrogen; D004958:Estradiol; D001192:Arylsulfatases; D043266:Steryl-Sulfatase