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γ‐Non‐Symmetrically Dimasked Tri PPP ro Prodrugs as Potential Antiviral Agents against HIV
Author(s) -
Zhao Chenglong,
Jia Xiao,
Schols Dominique,
Balzarini Jan,
Meier Chris
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000712
Subject(s) - prodrug , nucleoside , nucleoside analogue , thymidine kinase , chemistry , thymidine , nucleoside triphosphate , nucleoside reverse transcriptase inhibitor , nucleotide , enzyme , reverse transcriptase inhibitor , reverse transcriptase , biochemistry , stereochemistry , biology , virology , in vitro , virus , rna , herpes simplex virus , gene
Nucleoside analogue reverse transcriptase inhibitors (NRTI) and nucleoside analogue monophosphate prodrugs are used in combination antiretroviral therapy (cART). The design of antivirally active nucleoside triphosphate prodrugs is a recent and an important advancement in the field of nucleoside analogue drug development. Here, we report on Tri PPP ro‐derivatives of nucleoside analogue triphosphates (NTPs) that comprised two different acyloxybenzyl‐masks at the γ‐phosphate of the NTP aiming to achieve the metabolic bypass. Thus, γ‐non‐symmetrically dimasked Tri PPP ro‐compounds (γ‐(AB,ab)‐d4TTPs) were synthesized and they proved to be active against HIV‐1 and HIV‐2 in cultures of infected wild‐type human CD4 + T‐lymphocyte (CEM/0) cells and more importantly also in thymidine kinase‐deficient CD4 + T‐cells (CEM/TK‐). From hydrolysis studies both in phosphate buffer (PB, pH 7.3) and CEM cell extracts, there was surprisingly no differentiation in the cleavage of the two acyloxybenzyl prodrug‐masks. However, if within one of the two acyloxybenzyl groups a short PEG‐type methoxytriglycol group was introduced, the “standard” acyloxybenzyl‐mask was cleaved with high preference.