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

Kaczmarek, Renata ; Twardy, Dylan J. ; Olson, Trevor L. ; Korczyński, Dariusz ; Andrei, Graciela ; Snoeck, Robert ; Dolot, Rafał ; Wheeler, Kraig A. ; Dembinski, Roman

European journal of medicinal chemistry, 2021-01, Vol.209, p.112884-112884, Article 112884 [Periódico revisado por pares]

France: Elsevier Masson SAS

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Título:
Extension of furopyrimidine nucleosides with 5-alkynyl substituent: Synthesis, high fluorescence, and antiviral effect in the absence of free ribose hydroxyl groups
Autor: Kaczmarek, Renata ; Twardy, Dylan J. ; Olson, Trevor L. ; Korczyński, Dariusz ; Andrei, Graciela ; Snoeck, Robert ; Dolot, Rafał ; Wheeler, Kraig A. ; Dembinski, Roman
Assuntos: Alkynes ; Antiviral Agents - chemical synthesis ; Antiviral Agents - chemistry ; Antiviral Agents - pharmacology ; Antiviral chemotherapy ; Cell Line ; Fluorescence ; Furopyrimidines ; Halogenation ; Herpesvirus 3, Human - drug effects ; Humans ; Models, Molecular ; Modified nucleosides ; Pyrimidine Nucleosides - chemical synthesis ; Pyrimidine Nucleosides - chemistry ; Pyrimidine Nucleosides - pharmacology ; Research Paper ; Varicella Zoster Virus Infection - drug therapy ; Varicella Zoster Virus Infection - virology ; Varicella-zoster virus (VZV)
É parte de: European journal of medicinal chemistry, 2021-01, Vol.209, p.112884-112884, Article 112884
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Descrição: 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. Novel fluorescent nucleoside analogues, 5-alkynylfuropyrimidines show high quantum yields (0.53–0.60). Assays in VZV cell cultures are presented. [Display omitted] •A new synthetic protocol was established to access novel class of nucleosides, 6-alkynyl furopyrimidines•Antiviral activity in human embryonic lung (HEL) cell cultures against varicella-zoster virus (VZV)•Emission wavelength values 453–481 nm (λex = 360 nm) were observed for 6-alkynyl furopyrimidines•High quantum yields (0.53–0.60) observed for selected compounds•X-ray crystallography confirmed structure of 6-p-tolyl-5-iodo-2′-deoxyribofuranosyl-furo[2,3-d]pyrimidin-2-one
Editor: France: Elsevier Masson SAS
Idioma: Inglês

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

Kaczmarek, Renata ; Twardy, Dylan J. ; Olson, Trevor L. ; Korczyński, Dariusz ; Andrei, Graciela ; Snoeck, Robert ; Dolot, Rafał ; Wheeler, Kraig A. ; Dembinski, Roman

France: Elsevier Masson SAS

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