162332-45-8Relevant academic research and scientific papers
Synthesis, decomposition pathways and 'in vitro' evaluation of bioreversible phosphotriesters of AZT
Lefebvre,Pompon,Perigaud,Girardet,Gosselin,Aubertin -,Kirn,Imbach
, p. 763 - 766 (1995)
The synthesis, pharmacokinetic data and biological evaluation of a series of phosphotriesters containing S-acyl-2-thioethyl groups as enzyme-labile phosphate protecting groups and AZT as a model are described. A comparison of pharmacokinetic data and 'in vitro' experiments show that such bioreversible phosphotriesters of AZT are able to cross cell membranes and deliver the corresponding nucleoside monophosphate inside the cell. Moreover, kinetic data show that modification of the protecting groups can allow to modulate both the extracellular stability of the parent compond and the delivery of nucleoside monophosphate inside the cell.
Synthesis of nucleotide lipophilic prodrugs containing two inhibitors targeted against different phases of the HIV replication cycle
Bonnaffe,Dupraz,Ughetto-Monfrin,Namane,Dinh
, p. 783 - 787 (1995)
We describe the preparation of nucleoside acyl 5'-di or 5'-triphosphates, containing a nucleoside analog moiety and 13-oxa-myristic acid as lipophilic chain. At physiological pH these products liberated exclusively the corresponding nucleotides.
Lipophilic Triphosphate Prodrugs of Various Nucleoside Analogues
Jia, Xiao,Schols, Dominique,Meier, Chris
, p. 6991 - 7007 (2020/08/14)
The antiviral efficacy of many nucleoside analogues is strongly dependent on their intracellular activation by host cellular kinases to yield ultimately the bioactive nucleoside analogue triphosphates (NTP). The metabolic conversion of nucleoside analogues into their triphosphates often proceeds insufficiently. We developed a nucleoside triphosphate (NTP) delivery system (the TriPPPro approach), in which the γ-phosphate is covalently modified by two different biodegradable masking units, one is the acyloxybenzyl (AB) moiety and the other is the alkoxycarbonyloxybenzyl (ACB) group. Such compounds formed NTPs with high selectivity by an enzyme-triggered mechanism in human T-lymphocyte CEM cell extracts loosing first the AB moiety, followed by the ACB group. This enables the bypass of all steps of the intracellular phosphorylation. This approach was applied here to convert some modestly active or even inactive nucleoside analogues into powerful biologically active metabolites. Potent antiviral activity profiles were obtained depending on the lipophilicity of the TriPPPro-NTP prodrugs against HIV-1 and HIV-2 replication in cultures of infected wild-type CD4+ CEM T-cells and more importantly in thymidine kinase-deficient CD4+ T-cells (CEM/TK-). This TriPPPro strategy offers high potential for future antiviral and antitumoral chemotherapies.
