γ-Non-Symmetrically Dimasked TriPPPro Prodrugs as Potential Antiviral Agents against HIV.
ChemMedChem
; 16(3): 499-512, 2021 02 04.
Article
em En
| MEDLINE
| ID: mdl-33089929
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 TriPPPro-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 TriPPPro-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, pHâ
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.
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Base de dados:
MEDLINE
Assunto principal:
Fosfatos
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Pró-Fármacos
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HIV-1
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HIV-2
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Fármacos Anti-HIV
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Nucleosídeos
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article