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Synthesis and Anticancer and Antiviral Activities of C-2'-Branched Arabinonucleosides.
Bege, Miklós; Kiss, Alexandra; Bereczki, Ilona; Hodek, Jan; Polyák, Lenke; Szemán-Nagy, Gábor; Naesens, Lieve; Weber, Jan; Borbás, Anikó.
  • Bege M; Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary.
  • Kiss A; Institute of Healthcare Industry, University of Debrecen, Nagyerdei krt 98, 4032 Debrecen, Hungary.
  • Bereczki I; MTA-DE Molecular Recognition and Interaction Research Group, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary.
  • Hodek J; Department of Biotechnology and Microbiology, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary.
  • Polyák L; Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary.
  • Szemán-Nagy G; National Laboratory of Virology, University of Pécs, Ifjúság útja 20, 7624 Pécs, Hungary.
  • Naesens L; Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nam. 2, CZ-16000 Prague, Czech Republic.
  • Weber J; Department of Biotechnology and Microbiology, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary.
  • Borbás A; Department of Biotechnology and Microbiology, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary.
Int J Mol Sci ; 23(20)2022 Oct 19.
Article in English | MEDLINE | ID: covidwho-2081861
ABSTRACT
d-Arabinofuranosyl-pyrimidine and -purine nucleoside analogues containing alkylthio-, acetylthio- or 1-thiosugar substituents at the C2' position were prepared from the corresponding 3',5'-O-silylene acetal-protected nucleoside 2'-exomethylenes by photoinitiated, radical-mediated hydrothiolation reactions. Although the stereochemical outcome of the hydrothiolation depended on the structure of both the thiol and the furanoside aglycone, in general, high d-arabino selectivity was obtained. The cytotoxic effect of the arabinonucleosides was studied on tumorous SCC (mouse squamous cell) and immortalized control HaCaT (human keratinocyte) cell lines by MTT assay. Three pyrimidine nucleosides containing C2'-butylsulfanylmethyl or -acetylthiomethyl groups showed promising cytotoxicity at low micromolar concentrations with good selectivity towards tumor cells. SAR analysis using a methyl ß-d-arabinofuranoside reference compound showed that the silyl-protecting group, the nucleobase and the corresponding C2' substituent are crucial for the cell growth inhibitory activity. The effects of the three most active nucleoside analogues on parameters indicative of cytotoxicity, such as cell size, division time and cell generation time, were investigated by near-infrared live cell imaging, which showed that the 2'-acetylthiomethyluridine derivative induced the most significant functional and morphological changes. Some nucleoside analogues also exerted anti-SARS-CoV-2 and/or anti-HCoV-229E activity with low micromolar EC50 values; however, the antiviral activity was always accompanied by significant cytotoxicity.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Pyrimidine Nucleosides / Thiosugars / COVID-19 Type of study: Experimental Studies / Prognostic study / Randomized controlled trials Limits: Animals / Humans Language: English Year: 2022 Document Type: Article Affiliation country: Ijms232012566

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Pyrimidine Nucleosides / Thiosugars / COVID-19 Type of study: Experimental Studies / Prognostic study / Randomized controlled trials Limits: Animals / Humans Language: English Year: 2022 Document Type: Article Affiliation country: Ijms232012566