Synthesis and Cytostatic Effect of 3'-deoxy-3'-C-Sulfanylmethyl Nucleoside Derivatives with d-xylo Configuration

Miklós Bege, Alexandra Kiss, Máté Kicsák, Ilona Bereczki, Viktória Baksa, Gábor Király, Gábor Szemán-Nagy, M. Zsuzsa Szigeti, Pál Herczegh, Anikó Borbás

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3 Citations (Scopus)

Abstract

A small library of 3'-deoxy-C3'-substituted xylofuranosyl-pyrimidine nucleoside analogues were prepared by photoinduced thiol-ene addition of various thiols, including normal and branched alkyl-, 2-hydroxyethyl, benzyl-, and sugar thiols, to 3'-exomethylene derivatives of 2',5'-di-O-tert-butyldimethylsilyl-protected ribothymidine and uridine. The bioactivity of these derivatives was studied on tumorous SCC (mouse squamous carcinoma cell) and immortalized control HaCaT (human keratinocyte) cell lines. Several alkyl-substituted analogues elicited promising cytostatic activity in low micromolar concentrations with a slight selectivity toward tumor cells. Near-infrared live-cell imaging revealed SCC tumor cell-specific mitotic blockade via genotoxicity of analogue 10, bearing an n-butyl side chain. This analogue essentially affects the chromatin structure of SCC tumor cells, inducing a condensed nuclear material and micronuclei as also supported by fluorescent microscopy. The results highlight that thiol-ene chemistry represents an efficient strategy to discover novel nucleoside analogues with non-natural sugar structures as anticancer agents.

Original languageEnglish
Article number2173
JournalMolecules
Volume24
Issue number11
DOIs
Publication statusPublished - Jun 10 2019

Keywords

  • Cytostatic
  • Genotoxic
  • Radical thiol-ene coupling
  • Squamous carcinoma cell line (SCC)
  • Time-lapse imaging video-microscopy
  • Xylofuranosyl nucleoside

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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  • Cite this

    Bege, M., Kiss, A., Kicsák, M., Bereczki, I., Baksa, V., Király, G., Szemán-Nagy, G., Zsuzsa Szigeti, M., Herczegh, P., & Borbás, A. (2019). Synthesis and Cytostatic Effect of 3'-deoxy-3'-C-Sulfanylmethyl Nucleoside Derivatives with d-xylo Configuration. Molecules, 24(11), [2173]. https://doi.org/10.3390/molecules24112173