title: Synthesis of novel steroidal 16-spiroisoxazolines by 1,3-dipolar cycloaddition, and an evaluation of their antiproliferative activities in vitro.
abstract: Efficient synthesis of novel 16-spiroisoxazolines in the androst-5-ene series was carried out by 1,3-dipolar cycloadditions of different aryl nitrile oxides to 3β-acetoxy-16-methylene-androst-5-en-17-one. During the intermolecular ring closures, the attack of the O terminus of the nitrile oxide dipole from the α side on C-16 predominated for steric reasons permitting the reactions to occur in a regio- and stereoselective manner. The minor isomers in which the angular methyl group on C-13 and the O atom of the isoxazoline heteroring were in the β, β-cis orientation were obtained in a yield of only ~10 %. Moreover, the conversions were influenced to a certain extent by the substituents on the aromatic moiety of the 1,3-dipoles. The stereostructures of the related diastereomers were confirmed by 2D NMR methods. Deacetylation of the primarily formed main products resulted in the corresponding 3β-OH analogs, which were further reduced to furnish 3β, 17β-diols. All of the synthetized compounds were subjected to in vitro pharmacological studies in order to investigate their antiproliferative effects on three malignant human adherent cell lines (HeLa, MCF7, and A431).
authors.affiliation: Department of Organic Chemistry, University of Szeged, Dóm tér 8, Szeged, 6720, Hungary, frank@chem.u-szeged.hu.
authors.forename: Éva
authors.initials: É
authors.lastname: Frank
authors.forename: Dóra
authors.initials: D
authors.lastname: Kovács
authors.forename: Gyula
authors.initials: G
authors.lastname: Schneider
authors.forename: János
authors.initials: J
authors.lastname: Wölfling
authors.forename: Tibor
authors.initials: T
authors.lastname: Bartók
authors.forename: István
authors.initials: I
authors.lastname: Zupkó
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D061565:Cycloaddition Reaction; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D013141:Spiro Compounds / Q000737:chemistry*; D013237:Stereoisomerism; D013379:Substrate Specificity
chemical_list: D000970:Antineoplastic Agents; D007555:Isoxazoles; D013141:Spiro Compounds