Mononucleoside phosphotriester derivatives with S-acyl-2-thioethyl bioreversible phosphate-protecting groups: intracellular delivery of 3'-azido-2',3'-dideoxythymidine 5'-monophosphate.
The synthesis, in vitro anti-HIV-1 activity, and decomposition pathways of several mononucleoside phosphotriester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) incorporating a new kind of carboxylate esterase-labile transient phosphate-protecting group, namely, S-acyl-2-thioethyl, are reported. All the described compounds showed marked antiviral activity in thymidine kinase-deficient CEM cells in which AZT was virtually inactive. The results strongly support the hypothesis that such pronucleotides exert their biological effects via intracellular delivery of the 5'-mononucleotide of AZT. This point was corroborated by decomposition studies in cell extracts and culture medium.
Lefebvre
I
I
Laboratoire de Chimie Bioorganique, URA CNRS 488, Université Montpellier II, France.
Périgaud
C
C
Pompon
A
A
Aubertin
A M
AM
Girardet
J L
JL
Kirn
A
A
Gosselin
G
G
Imbach
J L
JL
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001692:Biological Transport; D002460:Cell Line; D054306:Dideoxynucleotides; D004355:Drug Stability; D015497:HIV-1 / Q000187:drug effects*; D013942:Thymine Nucleotides / Q000493:pharmacokinetics*; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D000998:Antiviral Agents; D054306:Dideoxynucleotides; D013942:Thymine Nucleotides; C057287:3'-azido-3'-deoxythymidine 5'phosphate; D015215:Zidovudine