N-Butyl-N-methyl-11-(3'-hydroxy-21', 17'-carbolactone-19'-nor-17'alpha-pregna-1',3', 5'(10')-trien-7'alpha-yl)-undecanamide: an inhibitor of type 2 17beta-hydroxysteroid dehydrogenase that does not have oestrogenic or androgenic activity.
It is well known that 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) play a key role in the formation and inactivation, from circulating precursors, of several active androgens and oestrogens. These enzymes can thus regulate tumoural cell proliferation in androgen- and oestrogen-dependent cancers. Recently, we discovered that adding a spiro-gamma-lactone to the oestradiol nucleus results in a novel inhibitor of type 2 17beta-HSD, an enzyme that catalyses the interconversions between 4-androstene-3,17-dione and testosterone, and between oestrone and oestradiol. This finding motivated our introducing the spiro-gamma-lactone moiety onto an anti-oestrogenic nucleus. The N-butyl-N-methyl-11-(3'-hydroxy-21', 17'-carbolactone-19'-nor-17'alpha-pregna-1',3', 5'(10')-trien-7'alpha-yl)-undecanamide (4) was then efficiently synthesized and its biological activity was assessed in vitro. Despite the presence of a bulky alkylamide side chain, the spiro-gamma-lactone function conserved its ability to inhibit type 2 17beta-HSD (IC(50) = 0.35 and 0.25 microM, with and without side chain, respectively). Furthermore, the selective inhibition by lactone 4 toward type 2 17beta-HSD (microsomal fraction of human placenta) was demonstrated by the absence of inhibitory activity toward type 1 17beta-HSD (cytosolic fraction of human placenta). Cell proliferation assays indicated that compound 4 had no oestrogenic activity but did show anti-oestrogenic activity on ER(+) cell line ZR-75-1. No androgenic activity could be detected when assayed on the AR(+) cell line Shionogi either. Based on these facts, we report the synthesis of a new steroidal derivative, one that inhibits type 2 17beta-HSD while possessing anti-oestrogenic activity.
Sam
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Medicinal Chemistry Division, Laboratory of Molecular Endocrinology, Laval University Medical Research Center, Centre hospitalier universitaire de Québec and Laval University, 2705 Laurier Boulevard, Québec, Canada.
Labrie
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Poirier
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D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D002455:Cell Division / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D045166:Estradiol Congeners / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D010920:Placenta / Q000201:enzymology; D011245:Pregnadienes / Q000138:chemical synthesis* / Q000494:pharmacology; D013055:Spectrophotometry, Infrared; D045165:Testosterone Congeners / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D045166:Estradiol Congeners; D004965:Estrogen Antagonists; C408966:N-butyl-N-methyl-11-(3'-hydroxy-21'-17'-carbolactone-19'-nor-17' -pregna-1',3',5'(10')-trien-7'-yl)-undecanamide; D011245:Pregnadienes; D045165:Testosterone Congeners; D015067:17-Hydroxysteroid Dehydrogenases