Schlienger N, Peyrottes S, Kassem T, Imbach J L, Gosselin G, Aubertin A M, Périgaud C
UMR 5625 CNRS-UM II, Université Montpellier II, cc 008, place E. Bataillon, 34095 Montpellier Cedex 05, France.
J Med Chem. 2000 Nov 16;43(23):4570-4. doi: 10.1021/jm000996o.
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.
报道了带有苯基或L-酪氨酰残基的3'-叠氮基-2',3'-双脱氧胸苷（AZT）的磷酸三酯衍生物的合成及其生物活性。目标化合物通过磷（V）或磷（III）化学方法由合适的芳基前体获得。对所有衍生物进行了体外抗HIV活性评估，在各种细胞培养实验中，它们似乎是HIV-1复制的有效抑制剂，其半数有效浓度（EC50）值在微摩尔至纳摩尔范围内。此外，含有氨基和/或酸取代酪氨酰残基的化合物在胸苷激酶缺陷（TK(-)）细胞中显示出显著的抗HIV作用，表明它们能够作为单核苷酸前药发挥作用。这些混合单核苷芳基磷酸三酯的分解过程可能包括酯酶激活，随后是磷酸二酯酶水解。
