title: A step further in the SATE mononucleotide prodrug approach.
abstract: 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 reported herein. These mononucleotide prodrugs (pronucleotides) are characterized by the presence of polar (amino or hydroxyl) functions on the SATE biolabile phosphate protections. Whereas pronucleotides 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 moiety confers high resistance of the resulting prodrugs towards esterase hydrolysis. Thus, one of these pronucleotides, derivative 2, was able to cross a Caco-2 cell monolayer mainly in intact form, probing that its further development is warranted as a possible HIV-pronucleotide candidate.
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-UM1-UM2, Université Montpellier 2, cc1705, Montpellier, France. peyrottes@univ-montp2.fr
authors.forename: S
authors.initials: S
authors.lastname: Peyrottes
authors.forename: A-L
authors.initials: AL
authors.lastname: Villard
authors.forename: G
authors.initials: G
authors.lastname: Coussot
authors.forename: P
authors.initials: P
authors.lastname: Augustijns
authors.forename: I
authors.initials: I
authors.lastname: Lefebvre
authors.forename: A-M
authors.initials: AM
authors.lastname: Aubertin
authors.forename: G
authors.initials: G
authors.lastname: Gosselin
authors.forename: C
authors.initials: C
authors.lastname: Périgaud
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001693:Biological Transport, Active; D018938:Caco-2 Cells; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006207:Half-Life; D006801:Humans; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011742:Pyrimidine Nucleotides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014779:Virus Replication; D015215:Zidovudine / Q000031:analogs & derivatives*
chemical_list: D019380:Anti-HIV Agents; D011355:Prodrugs; D011742:Pyrimidine Nucleotides; D015215:Zidovudine