UMR CNRS-ENS-UPMC 8640 PASTEUR and LIA CNRS XiamENS, Ecole Normale Supérieure, 24 rue Lhomond, 75231 Paris Cedex 5, France.
ChemMedChem. 2010 Feb 1;5(2):296-301. doi: 10.1002/cmdc.200900464.
Zidovudine (azidothymidine, AZT) was the first drug approved for human immunodeficiency virus (HIV) treatment. Unfortunately, AZT is known to lead to severe side effects, many of which are generally thought to result from increased reactive oxygen species (ROS) production. In this work, the pro-oxidative properties of AZT and other thymidine analogues were investigated electrochemically at microelectrodes. Macrophages pre-incubated with AZT were found to release significant amounts of reactive species, including H(2)O(2), ONOO(-), NO(*) and NO(2) (-). Interestingly, the total amounts of released species were the greatest when cells were incubated with azido-containing analogues. The pro-oxidative effect of these compounds decreased significantly when the free azide terminal group was modified by reaction with a triosmium cluster. As expected, thymidine incubation did not lead to any increase in overall ROS levels. This work implicates the azido moiety in AZT-induced oxidative stress.
齐多夫定（叠氮胸苷，AZT）是第一种被批准用于治疗人类免疫缺陷病毒（HIV）的药物。不幸的是，AZT 已知会导致严重的副作用，其中许多通常被认为是由于活性氧（ROS）产生增加所致。在这项工作中，AZT 和其他胸苷类似物的促氧化性质在微电极上进行了电化学研究。发现用 AZT 预孵育的巨噬细胞会释放大量的反应性物质，包括 H（2）O（2）、ONOO（-）、NO（*）和 NO（2）（-）。有趣的是，当细胞与含叠氮的类似物孵育时，释放的物质总量最大。当游离叠氮末端基团与三锇簇反应修饰时，这些化合物的促氧化作用显著降低。正如预期的那样，胸苷孵育不会导致 ROS 水平的总体增加。这项工作表明 AZT 诱导的氧化应激与叠氮基团有关。
