Peyrottes S, Villard A-L, Coussot G, Augustijns P, Lefebvre I, Aubertin A-M, Gosselin G, Périgaud C
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-UM1-UM2, Université Montpellier 2, cc1705, Montpellier, France.
Nucleic Acids Symp Ser (Oxf). 2008(52):539-40. doi: 10.1093/nass/nrn273.
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.
本文报道了一些新型齐多夫定（叠氮胸苷；3'-叠氮-2',3'-双脱氧胸苷）的苯基S-酰基-2-硫代乙基（SATE）磷酸三酯衍生物的合成、体外抗HIV活性、稳定性研究以及口服吸收潜力。这些单核苷酸前药（前核苷酸）的特点是在SATE生物可裂解的磷酸保护基上存在极性（氨基或羟基）官能团。虽然在硫酯官能团附近含有氨基残基的前核苷酸显示出低化学稳定性，但在SATE部分引入一个或两个羟基会使所得前药对酯酶水解具有高抗性。因此，这些前核苷酸之一，衍生物2，能够主要以完整形式穿过Caco-2细胞单层，表明其作为一种可能的HIV前核苷酸候选物值得进一步开发。
