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Synthesis of 1,2,3-Triazole-Containing Furanosyl Nucleoside Analogs and Their Phosphate, Phosphoramidate or Phoshonate Derivatives as Potential Sugar Diphosphate or Nucleotide Mimetics

preprint
submitted on 20.05.2020 and posted on 21.05.2020 by Andreia Fortuna, Paulo J. Costa, Fátima Piedade, M. Conceição Oliveira, Nuno Manuel Xavier

The synthesis of a variety of novel, rather stable and potentially bioactive nucleoside analogs and nucleotide mimetics based on xylofuranose scaffolds and comprising a 1,2,3-triazole moiety as a surrogate for a nucleobase or a phosphate group is reported. Isonucleosides embodying a 3-O-(benzyltriazolyl)methyl moiety at C-3 were accessed by using the Cu(I)-catalyzed “click” 1,3-dipolar cycloaddition between 3-O-propargyl-1,2-O-isopropylidene-α-D-xylofuranose and benzyl azide as the key step. Related isonucleotides comprising a phosphate or a phosphoramidate moiety at C-5 were obtained via 5-O-phosphorylation of acetonide-protected 3-O-propargyl xylofuranose followed by “click” cycloaddition or by Staudinger reaction of a 5ʹ-azido N-benzyltriazole isonucleoside with triethyl phosphite, respectively. Hydroxy, amino- or bromomethyl triazole 5ʹ-isonucleosides were synthesized through thermal cycloaddition between 5-azido 3-O-benzyl/dodecyl-1,2-O-isopropylidene-α-D-xylofuranoses and propargyl alcohol, propargylamine or propargyl bromide, respectively. The regiochemical outcome of the cycloaddition reactions was influenced by nature of the alkyne hetero substituent (alkyne CH2X substituent). The 5´-isonucleosides were converted into their [(xylofuranos-5-yl)triazolyl]methyl phosphate, phosphoramidate and phosphonate derivatives as prospective sugar diphosphate mimetics by an appropriate method involving treatment with diethyl phosphorochloridate or a Michaelis-Arbuzov reaction. 4-Phosphonomethyl-1-xylofuranos-5ʹ-yl triazoles were converted into 1,2-O-acetyl glycosyl donors and subsequently subjected to nucleosidation with uracil leading to the corresponding uracil nucleoside 5ʹ-(triazolyl)methyl phosphonates, whose structure potentially mimics that of a nucleoside diphosphate.

Funding

IF/01488/2013/CP1159/CT0006

IF/00069/2014/CP1216/CT0006

UIDB/00100/2020

UIDP/00100/2020

UID/MULTI/04046/2019

UIDB/04046/2020

UIDP/04046/2020

UID/MULTI/00612/2013

UID/MULTI/00612/2019

LISBOA-01-0145-FEDER-028455

PTDC/QUI-QFI/28455/2017

History

Email Address of Submitting Author

nmxavier@fc.ul.pt

Institution

Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa

Country

Portugal

ORCID For Submitting Author

0000-0001-8739-8768

Declaration of Conflict of Interest

No conflict of interest

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