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Synthesis of novel steroidal 16-spiroisoxazolines by 1,3-dipolar cycloaddition, and an evaluation of their antiproliferative activities in vitro

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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 3\(\upbeta \)-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 \(\upalpha \) 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 \(\upbeta \), \(\upbeta \)-cis orientation were obtained in a yield of only \(\sim \)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 3\(\upbeta \)-OH analogs, which were further reduced to furnish 3\(\upbeta \), 17\(\upbeta \)-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).

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Acknowledgments

The financial support by the Hungarian Scientific Research Fund (OTKA K-109107) and the New Hungary Development Plan (TÁMOP-4.2.2.A-11/1/KONV-2012-0047) is gratefully acknowledged. The research by D. Kovács was supported by the European Union and the State of Hungary, co-financed by the European Social Fund in the framework of TÁMOP-4.2.4.A/2-11/1-2012-0001 “National Excellence Program”.

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Authors and Affiliations

  1. Department of Organic Chemistry, University of Szeged, Dóm tér 8, Szeged, 6720, Hungary

    Éva Frank, Dóra Kovács, Gyula Schneider & János Wölfling

  2. Faculty of Engineering, University of Szeged, Moszkvai krt. 5-7, Szeged, 6725, Hungary

    Tibor Bartók

  3. Fumizol Ltd., Moszkvai krt. 5-7, Szeged, 6725, Hungary

    Tibor Bartók

  4. Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös u. 6, Szeged, 6720, Hungary

    István Zupkó

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  1. Éva Frank
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  4. János Wölfling
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Correspondence to Éva Frank.

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Frank, É., Kovács, D., Schneider, G. et al. Synthesis of novel steroidal 16-spiroisoxazolines by 1,3-dipolar cycloaddition, and an evaluation of their antiproliferative activities in vitro. Mol Divers 18, 521–534 (2014). https://doi.org/10.1007/s11030-014-9516-8

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