title: Synthesis of novel 17-(4'-formyl)pyrazolylandrosta-5,16-dienes and their derivatives as potent 17α-hydroxylase/C17,20-lyase inhibitors or antiproliferative agents depending on the substitution pattern of the heteroring.
abstract: A series of novel 17-(4'-formyl)pyrazolylandrosta-5,16-dienes were efficiently synthesized in two steps from pregnadienolone acetate with monosubstituted hydrazines via the cyclization/formylation sequence of the primarily formed hydrazones on treatment with the Vilsmeier-Haack reagent. The products were further transformed by deacetylation and subsequent reduction in order to enlarge the compound library available for pharmacological studies. Moreover, 4'-formylpyrazoles containing H or Me on the heteroring-N were subjected to oxime formation and Ac2O-induced dehydration to furnish the corresponding 4'-cyano derivatives in good yields. The antiproliferative activities of the structurally related steroidal 17-exo-pyrazole derivatives were tested in vitro on four human adherent breast cancer cell lines (MCF7, T47D, MDA-MB-231 and MDA-MB-361): the microculture tetrazolium assay revealed that seven compounds exerted better cell growth-inhibitory effects on some or all these cell lines than those of the reference cisplatin. With regard to the well-known structural features that a potent C17,20-lyase inhibitor should possess, some relevant derivatives were tested in vitro from the aspects of their inhibitory effects on rat testicular enzyme, and one of them proved to exert noteworthy enzyme-inhibitory action, with an IC50 (26 nM) of the same order of magnitude as that of abiraterone.
authors.affiliation: Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720, Szeged, Hungary.
authors.forename: Dóra
authors.initials: D
authors.lastname: Kovács
authors.affiliation: Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720, Szeged, Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Wölfling
authors.affiliation: 1st Department of Medicine, University of Szeged, Korányi fasor 8-10, H-6720, Szeged, Hungary.
authors.forename: Nikoletta
authors.initials: N
authors.lastname: Szabó
authors.affiliation: 1st Department of Medicine, University of Szeged, Korányi fasor 8-10, H-6720, Szeged, Hungary.
authors.forename: Mihály
authors.initials: M
authors.lastname: Szécsi
authors.affiliation: Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös u. 6, H-6720, Szeged, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Schelz
authors.affiliation: Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös u. 6, H-6720, Szeged, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Zupkó
authors.affiliation: Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720, Szeged, Hungary. Electronic address: frank@chem.u-szeged.hu.
authors.forename: Éva
authors.initials: É
authors.lastname: Frank
mesh_terms: D000730:Androstadienes / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D006834:Hydrazines; D008190:Lyases / Q000037:antagonists & inhibitors; D008297:Male; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D013256:Steroids; D013329:Structure-Activity Relationship
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006834:Hydrazines; D011720:Pyrazoles; D013256:Steroids; D013254:Steroid 17-alpha-Hydroxylase; D008190:Lyases
keywords: Antiproliferative effect; C(17,20)-lyase inhibition; Pyrazoles; Steroids; Vilsmeier-Haack formylation