gamma-Non-symmetrically-dimasked TriPPPro-prodrugs as potential antivirals against HIV.

gamma-Non-symmetrically-dimasked TriPPPro-prodrugs as potential antivirals against HIV.
ChemMedChem. 2020 Oct 22;:
Authors: Zhao C, Jia X, Schols D, Balzarini J, Meier C
Abstract
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.
PMID: 33089929 [PubMed - as supplied by publisher]

Source: ChemMedChem - October 22, 2020 Category: Chemistry Authors: Zhao C, Jia X, Schols D, Balzarini J, Meier C Tags: ChemMedChem Source Type: research