2. Academic Validation
  3. Extension of furopyrimidine nucleosides with 5-alkynyl substituent: Synthesis, high fluorescence, and antiviral effect in the absence of free ribose hydroxyl groups

Extension of furopyrimidine nucleosides with 5-alkynyl substituent: Synthesis, high fluorescence, and antiviral effect in the absence of free ribose hydroxyl groups

  • Eur J Med Chem. 2021 Jan 1:209:112884. doi: 10.1016/j.ejmech.2020.112884.
Renata Kaczmarek 1,  Dylan J Twardy 2,  Trevor L Olson 2,  Dariusz Korczyński 1,  Graciela Andrei 3,  Robert Snoeck 3,  Rafał Dolot 1,  Kraig A Wheeler 4,  Roman Dembinski 5
Affiliations

Affiliations

  • 1 Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363, Łódź, Poland.
  • 2 Department of Chemistry, Oakland University, 146 Library Drive, Rochester, MI, 48309-4479, USA.
  • 3 Rega Institute, Department of Microbiology, Immunology and Transplantation, Herestraat 49, 3000, Leuven, Belgium.
  • 4 Department of Chemistry, Whitworth University, 300 W. Hawthorne Rd., Spokane, WA, 99251, USA.
  • 5 Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363, Łódź, Poland; Department of Chemistry, Oakland University, 146 Library Drive, Rochester, MI, 48309-4479, USA. Electronic address: dembinsk@oakland.edu.
PMID: 33039724 DOI: 10.1016/j.ejmech.2020.112884
Abstract

A novel methodology to access alkynyl nucleoside analogues is elaborated. Highly fluorescent 5-alkynylfuropyrimidines were synthesized (97-46%) and their Antiviral properties investigated in vitro. Regiochemistry of the functionalization was achieved with the aid of 5-endo-dig electrophilic halocyclization of acetyl 5-p-tolyl- or 5-p-pentylphenyl-2'-deoxyuridine. Structure of one of the resulting nucleosides, 6-p-tolyl-5-iodo-2'-deoxyribofuranosyl-furo[2,3-d]pyrimidin-2-one, was confirmed by X-ray crystallography, and its conformation was compared to related nucleosides. Diverse alkynyl substituents were introduced at the heterobicyclic base C-5 position via Sonogashira coupling of 5-iodo-2'-deoxyribofuranosyl-furo[2,3-d]pyrimidin-2-ones. The resulting compounds had fluorescence emissions of 452-481 nm. High quantum yields of 0.53-0.60 were observed for 9-ethynyl-9-fluorenol and propargyl alcohol/methyl ether-modified furopyrimidines. These modified nucleosides, designed in the form of ribose acetyl esters, are potential tools for fluorescent tagging, studying nucleoside metabolism, 2'-deoxyribonucleoside kinase activity, and Antiviral activity. Antiviral assays against a broad spectrum of DNA and RNA viruses showed that in human embryonic lung (HEL) cell cultures some of the compounds posess Antiviral activity (EC50 1.3-13.2 μM) against varicella-zoster virus (VZV). The alkynyl furopyrimidine with two p-pentylphenyl substituents emerged as the best compound with reasonable and selective anti-VZV activity, confirming p-pentylphenyl potency as a pharmacophore.

Keywords

Alkynes; Antiviral chemotherapy; Furopyrimidines; Modified nucleosides; Varicella-zoster virus (VZV).

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