title: Efficient access to novel androsteno-17-(1',3',4')-oxadiazoles and 17β-(1',3',4')-thiadiazoles via N-substituted hydrazone and N,N'-disubstituted hydrazine intermediates, and their pharmacological evaluation in vitro.
abstract: A series of novel 17-exo-oxadiazoles and -thiadiazoles in the Δ(5) androstene series were efficiently synthesized from pregnenolone acetate and pregnadienolone acetate via multistep pathways. 17β-(1',3',4')-Oxadiazoles were obtained in high yields by the phenyliodonium diacetate-induced oxidative ring closure of semicarbazone and N-acylhydrazones derived from 3β-acetoxy- and 3β-hydroxyandrost-5-ene-17β-carbaldehydes. For the synthesis of analogous Δ(16)-17-oxadiazolyl derivatives, N,N'-disubstituted hydrazine intermediates were prepared from 3β-acetoxyandrosta-5,16-diene-17-carboxylic acid, which then underwent cyclodehydration in the presence of POCl3. The cyclization of steroidal N,N'-diacylhydrazines containing a saturated ring D with the Lawesson reagent afforded 17β-(1',3',4')-thiadiazoles in good yields. Most of the products were subjected to deacetylation in basic media in order to enlarge the compound library available for pharmacological studies. All of these derivatives were screened in vitro for their antiproliferative effects against four malignant human adherent cell lines (HeLa, A2780, MCF7 and A431) by means of the MTT assay. The 3β-hydroxy derivatives of the newly-synthesized 17-exo-heterocycles were tested in vitro to investigate their inhibitory effects on rat testicular C17,20-lyase. One of the 1,3,4-oxadiazolyl derivatives proved to exert noteworthy enzyme-inhibitory action, with an IC50 (0.065 μM) 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: Renáta
authors.initials: R
authors.lastname: Minorics
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: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006834:Hydrazines / Q000737:chemistry* / Q000494:pharmacology*; D006835:Hydrazones / Q000737:chemistry* / Q000494:pharmacology*; D066298:In Vitro Techniques; D010069:Oxadiazoles / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D006834:Hydrazines; D006835:Hydrazones; D010069:Oxadiazoles; D013830:Thiadiazoles; C029424:hydrazine
keywords: 1,3,4-Oxadiazole; 1,3,4-Thiadiazole; Antiproliferative activity; P450(17α) inhibition; Steroids