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

2019; Multidisciplinary Digital Publishing Institute; Volume: 24; Issue: 11 Linguagem: Inglês

10.3390/molecules24112173

1433-1373

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

Click Chemistry and Applications

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.