S-acyl-2-thioethyl phosphoramidate diester derivatives as mononucleotide prodrugs.
The synthesis and in vitro anti-HIV activity of phosphoramidate diester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) bearing one S-pivaloyl-2-thioethyl (tBuSATE) group and various amino residues are reported. These compounds were obtained from an H-phosphonate strategy using an amidative oxidation step. Most of these derivatives appeared to inhibit HIV-1 replication, with EC(50) values at micromolar concentration in thymidine kinase-deficient (TK-) cells, revealing a less restrictive intracellular decomposition process than previously reported for other phosphoramidate prodrugs. The proposed decomposition pathway of this new series of mixed pronucleotides may successively involve an esterase and a phosphoramidase hydrolysis.
Egron
David
D
UMR 5625 CNRS-UM II, Université Montpellier II, case courrier 008, place E. Bataillon, 34095 Montpellier Cedex 5, France.
Imbach
Jean-Louis
JL
Gosselin
Gilles
G
Aubertin
Anne-Marie
AM
Périgaud
Christian
C
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology*; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D007202:Indicators and Reagents; D009943:Organophosphorus Compounds; D011355:Prodrugs; D013937:Thymidine Kinase