title: Synthesis and steroid sulphatase inhibitory activity of C19- and C21-steroidal derivatives bearing a benzyl-inhibiting group.
abstract: Two series of compounds, benzyl alkylated at position 17alpha and 20 of androstane and pregnane, respectively, were synthesised and tested for steroid sulphatase inhibition. We compared the ability of the compounds to inhibit steroid sulphatase obtained from two different sources (homogenates of transfected HEK-293 cells and Jeg-3 cells) and with two types of substrate (DHEAS or E(1)S). The inhibitory activity of 17alpha-benzyl-5alpha-androstane-3beta,17beta-diol (7), 17alpha-benzyl-5-androstene-3beta,17beta-diol (9), 17alpha-benzyl-4,17beta-dihydroxy-4-androsten-3-one (15) and 20-benzyl-5-pregnene-3beta,20alpha-diol (16) has proven to be superior to that of danazol, the first steroid sulphatase inhibitor to be reported, but still lower than that of the potent inhibitor estrone-3-O-sulphamate. The inhibitory activity of compound 7 was as potent as that of its previously reported estrane analogue, 17alpha-benzyl estradiol. Benzyl alkylated compounds with no OH group on the A-ring (with a 4-OCH(3), 4-Cl, or 4-H and their precursor epoxides), as well as a series of basic steroids without a benzyl group (ADT, epi-ADT, 3alpha-diol, 3beta-diol, DHEA, Delta(5)-diol, DHT, T, Preg and Prog), did not show steroid sulphatase inhibition. We have thus demonstrated that the steroid sulphatase inhibitory effect of a benzyl group, previously observed for an estrane nucleus, can be extended to certain androstane and pregnane nuclei bearing a 3beta-OH or a 4-OH group. Inhibitors 7, 9, 15 and 16 did not induce any proliferative effect on androgen-sensitive Shionogi cells. However, when tested on oestrogen-sensitive ZR-75-1 cells, a proliferative effect was observed for 7 and 9, but not for 15 and 16.
authors.affiliation: Medicinal Chemistry Division, Oncology and Molecular Endocrinology Research Center, Centre Hospitalier Universitaire de Québec (CHUQ), Pavillon CHUL, Québec, G1V 4G2, Sainte-Foy, Canada.
authors.forename: L C
authors.initials: LC
authors.lastname: Ciobanu
authors.forename: R P
authors.initials: RP
authors.lastname: Boivin
authors.forename: V
authors.initials: V
authors.lastname: Luu-The
authors.forename: D
authors.initials: D
authors.lastname: Poirier
mesh_terms: D000731:Androstanes / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D001192:Arylsulfatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001554:Benzene / Q000737:chemistry; D002460:Cell Line / Q000166:cytology / Q000378:metabolism; D019314:Dehydroepiandrosterone Sulfate / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000378:metabolism; D051379:Mice; D011278:Pregnanes / Q000138:chemical synthesis / Q000494:pharmacology; D013256:Steroids / Q000138:chemical synthesis / Q000494:pharmacology; D043266:Steryl-Sulfatase; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000378:metabolism
chemical_list: C445526:17-benzyl-5-androstane-3,17-diol; D000731:Androstanes; D004791:Enzyme Inhibitors; D011278:Pregnanes; D013256:Steroids; D019314:Dehydroepiandrosterone Sulfate; D001192:Arylsulfatases; D043266:Steryl-Sulfatase; D001554:Benzene