title: An efficient approach to novel 17-5'-(1',2',4')-oxadiazolyl androstenes via the cyclodehydration of cytotoxic O-steroidacylamidoximes, and an evaluation of their inhibitory action on 17α-hydroxylase/C₁₇,₂₀-lyase.
abstract: Novel 17-exo-oxadiazoles in the androst-5-ene series were efficiently synthesized in a two-step sequence via the corresponding O-acylamidoxime intermediates (obtained from steroidal 17-carboxylic acids and amidoximes in the presence of coupling reagent), which then underwent tetrabutylammonium fluoride-induced cyclocondensation under mild reaction conditions. The synthesized compounds were subjected to in vitro pharmacological studies to investigate their inhibitory effect on rat testicular C₁₇,₂₀-lyase and their antiproliferative action on four malignant human adherent cell lines (HeLa, MCF7, A2780 and A431). One of the oxadiazolyl derivatives proved to exert significant enzyme-inhibitory action (IC₅₀ = 0.60 μM), while some of the isolated O-acylated amidoxime intermediates displayed high cytotoxic activities on all examined cell lines, with IC₅₀ values in the range 0.22-3.94 μM.
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.forename: János
authors.initials: J
authors.lastname: Wölfling
authors.forename: Nikoletta
authors.initials: N
authors.lastname: Szabó
authors.forename: Mihály
authors.initials: M
authors.lastname: Szécsi
authors.forename: Ida
authors.initials: I
authors.lastname: Kovács
authors.forename: István
authors.initials: I
authors.lastname: Zupkó
authors.forename: Eva
authors.initials: E
authors.lastname: Frank
mesh_terms: D000736:Androstenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003500:Cyclization; D003681:Dehydration; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D008968:Molecular Conformation; D010091:Oximes / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013737:Testis / Q000201:enzymology / Q000378:metabolism
chemical_list: D000736:Androstenes; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010091:Oximes; D013254:Steroid 17-alpha-Hydroxylase
keywords: 1,2,4-Oxadiazoles; Antiproliferative activity; O-Acylamidoximes; P450(17α) inhibitor; Steroids