S-Acyl-2-thioethyl aryl phosphotriester derivatives as mononucleotide prodrugs.
The synthesis and biological activities of phosphotriester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) bearing a phenyl group or L-tyrosinyl residues are reported. The target compounds were obtained via either P(V) or 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. Furthermore, compounds incorporating an amino- and/or acid-substituted tyrosinyl residue demonstrated significant anti-HIV effects in thymidine kinase-deficient (TK(-)) cells showing their ability to act as mononucleotide prodrugs. The proposed decomposition process of these mixed mononucleoside aryl phosphotriesters may involve esterase activation followed by phosphodiesterase hydrolysis.
Schlienger
N
N
UMR 5625 CNRS-UM II, Université Montpellier II, cc 008, place E. Bataillon, 34095 Montpellier Cedex 05, France.
Peyrottes
S
S
Kassem
T
T
Imbach
J L
JL
Gosselin
G
G
Aubertin
A M
AM
Périgaud
C
C
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects; D006868:Hydrolysis; D010755:Organophosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000172:deficiency; D014779:Virus Replication; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D019380:Anti-HIV Agents; D010755:Organophosphates; D011355:Prodrugs; D015215:Zidovudine; D013937:Thymidine Kinase