Phenyl phosphotriester derivatives of AZT: variations upon the SATE moiety.
Synthesis, in vitro anti-HIV activity, stability studies as well as potential for oral absorption of some novel phenyl S-acyl-2-thioethyl (SATE) phosphotriester derivatives of AZT (zidovudine; 3'-azido-2',3'-dideoxythymidine) are described herein. These pronucleotides are characterized by the presence of polar functions on the SATE biolabile phosphate protections. Whereas derivatives incorporating an amino residue in the vicinity of the thioester functionality display low chemical stability, the introduction of one or two hydroxyl groups on the SATE moieties confers high resistance of the resulting prodrugs towards esterase hydrolysis. Thus, one of these pronucleotides, the monohydroxylated SATE derivative of AZT 2, is able to cross a Caco-2 cell monolayer mainly in intact form, probing that further development is warranted as a possible HIV-pronucleotide candidate.
Villard
Anne-Laure
AL
Institut des Biomolécules Max Mousseron, UMR 5247 CNRS-UM 1 & 2, Université Montpellier 2, Case courrier 1705, place E. Bataillon, 34095 Montpellier Cedex 5, France.
Coussot
Gaëlle
G
Lefebvre
Isabelle
I
Augustijns
Patrick
P
Aubertin
Anne-Marie
AM
Gosselin
Gilles
G
Peyrottes
Suzanne
S
Périgaud
Christian
C
D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D018938:Caco-2 Cells; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D015215:Zidovudine / Q000737:chemistry* / Q000494:pharmacology*
D019380:Anti-HIV Agents; D015215:Zidovudine