S-acyl-2-thioethyl aryl phosphotriester derivatives of AZT: synthesis, antiviral activity, and stability study.
The synthesis, antiviral activity, and stability study of phosphotriester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) bearing modified l-tyrosinyl residues are reported. These compounds were obtained via phosphoramidite (P(III)) chemistry from the appropriate aryl precursors. All the derivatives were evaluated for their in vitro anti-HIV activity, and they appeared to be potent inhibitors of HIV-1 replication in various cell culture experiments, with EC(50) values between the micro- and nanomolar range, especially in thymidine kinase deficient (TK(-)) cells, showing their ability to act as mononucleotide prodrugs. The proposed decomposition process of these mixed mononucleoside aryl phosphotriesters successively involves an esterase and a phosphodiesterase hydrolysis.
Peyrottes
Suzanne
S
UMR 5625 CNRS-UMII, Université Montpellier II, Case Courrier 008, Place Eugène Bataillon, 34095 Montpellier Cedex 05, France.
Coussot
Gaëlle
G
Lefebvre
Isabelle
I
Imbach
Jean-Louis
JL
Gosselin
Gilles
G
Aubertin
Anne-Marie
AM
Périgaud
Christian
C
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002457:Cell Extracts; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D010755:Organophosphates / Q000138:chemical synthesis* / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D013440:Sulfides / Q000138:chemical synthesis* / Q000494:pharmacology; D014779:Virus Replication; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
D019380:Anti-HIV Agents; D002457:Cell Extracts; D010755:Organophosphates; D013440:Sulfides; D015215:Zidovudine