1. A step further in the SATE mononucleotide prodrug approach.
- Author
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Peyrottes S, Villard AL, Coussot G, Augustijns P, Lefebvre I, Aubertin AM, Gosselin G, and Périgaud C
- Subjects
- Anti-HIV Agents metabolism, Anti-HIV Agents pharmacology, Biological Transport, Active, Caco-2 Cells, Cell Line, HIV-1 drug effects, HIV-1 physiology, Half-Life, Humans, Prodrugs metabolism, Prodrugs pharmacology, Pyrimidine Nucleotides chemistry, Pyrimidine Nucleotides metabolism, Pyrimidine Nucleotides pharmacology, Virus Replication, Anti-HIV Agents chemistry, Prodrugs chemistry, Zidovudine analogs & derivatives
- 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.
- Published
- 2008
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