Synthesis and Cytostatic Effect of 3’-deoxy-3’-<i>C</i>-Sulfanylmethyl Nucleoside Derivatives with <span style="font-variant: small-caps">d</span>-<i>xylo</i> Configuration
Miklós Bege,
Alexandra Kiss,
Máté Kicsák,
Ilona Bereczki,
Viktória Baksa,
Gábor Király,
Gábor Szemán-Nagy,
M. Zsuzsa Szigeti,
Pál Herczegh,
Anikó Borbás
Affiliations
Miklós Bege
Department of Pharmaceutical Chemistry, University of Debrecen, 4032 Debrecen, Egyetem Tér 1, Hungary
Alexandra Kiss
Department of Biotechnology and Microbiology, University of Debrecen, 4032 Debrecen, Egyetem Tér 1, Hungary
Máté Kicsák
Department of Pharmaceutical Chemistry, University of Debrecen, 4032 Debrecen, Egyetem Tér 1, Hungary
Ilona Bereczki
Department of Pharmaceutical Chemistry, University of Debrecen, 4032 Debrecen, Egyetem Tér 1, Hungary
Viktória Baksa
Department of Biotechnology and Microbiology, University of Debrecen, 4032 Debrecen, Egyetem Tér 1, Hungary
Gábor Király
Department of Biotechnology and Microbiology, University of Debrecen, 4032 Debrecen, Egyetem Tér 1, Hungary
Gábor Szemán-Nagy
Department of Biotechnology and Microbiology, University of Debrecen, 4032 Debrecen, Egyetem Tér 1, Hungary
M. Zsuzsa Szigeti
Department of Biotechnology and Microbiology, University of Debrecen, 4032 Debrecen, Egyetem Tér 1, Hungary
Pál Herczegh
Department of Pharmaceutical Chemistry, University of Debrecen, 4032 Debrecen, Egyetem Tér 1, Hungary
Anikó Borbás
Department of Pharmaceutical Chemistry, University of Debrecen, 4032 Debrecen, Egyetem Tér 1, Hungary
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.
