title: Synthesis of antiproliferative 13α-d-homoestrones via Lewis acid-promoted one-pot Prins-Ritter reactions of d-secosteroidal δ-alkenyl-aldehydes.
abstract: A simple one-pot Prins-Ritter route was developed for the synthesis of 16-acylamino-17a-hydroxy-d-homoestrone 3-benzyl and 3-methyl ethers in the 13α-estrone series. The d-secosteroidal δ-alkenyl-aldehydes were allowed to react with different nitriles in the presence of BF3·OEt2 as a Lewis acid catalyst. Prins cyclizations afforded 17a-hydroxy-16-carbenium ions, which underwent Ritter reactions with nitriles, leading to 16α- or 16β-acylamino derivatives. A side-product in which a dihydro-1,3-oxazine was bridged to six-membered ring D at positions 16α,17aα was formed in each reaction. The antiproliferative properties of the novel 13α-d-homosteroids were determined on a panel of human adherent cancer cell lines (HeLa, MCF-7, T47D, MDA-MB-231, MDA-MB-361, A2780 and A431) by means of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assays. Some compounds proved to be more effective (with submicromolar IC50 values) than the reference agent cisplatin. One of the most potent compounds substantially increased the rate of tubulin polymerization. Cell cycle analyses by flow cytometry indicated a concentration-dependent accumulation of the G2/M cell population.
authors.affiliation: Department of Organic Chemistry, University of Szeged, Dóm tér 8., H-6720 Szeged, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Huber
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: Department of Organic Chemistry, University of Szeged, Dóm tér 8., H-6720 Szeged, Hungary.
authors.forename: Gyula
authors.initials: G
authors.lastname: Schneider
authors.affiliation: Department of Biochemistry, University of Szeged, Dóm tér 9., H-6720 Szeged, Hungary.
authors.forename: Imre
authors.initials: I
authors.lastname: Ocsovszki
authors.affiliation: Cereal Research Non-Profit Ltd., P.O. Box 391, H-6701 Szeged, Hungary.
authors.forename: Mónika
authors.initials: M
authors.lastname: Varga
authors.affiliation: Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös u. 6., H-6720 Szeged, Hungary. Electronic address: zupko@pharm.u-szeged.hu.
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: bobe@chem.u-szeged.hu.
authors.forename: Erzsébet
authors.initials: E
authors.lastname: Mernyák
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004963:Estrenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells
chemical_list: D000970:Antineoplastic Agents; D004963:Estrenes
keywords: Antiproliferative; Azabicyclononene; Dihydro-1,3-oxazine; One-pot; Prins–Ritter; d-Homoestrone