Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, Department of Medicinal Chemistry, School of Pharmacy, Tianjin Medical University, Tianjin 300070, P. R. China.
Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary.
J Org Chem. 2021 Jun 18;86(12):8351-8364. doi: 10.1021/acs.joc.1c00766. Epub 2021 May 27.
Tetrathiatriarylmethyl (trityl) radicals have been recently shown to react with biological oxidoreductants including glutathione (GSH), ascorbic acid (Asc), and superoxide anion radical (O). However, how the substituents affect the reactivity of trityl radicals is still unknown. In this work, five asymmetric trityl radicals were synthesized and their reactivities with GSH, Asc, and O investigated. Under aerobic conditions, GSH induces fast decays for the thioether- (TSA) and -methyleneglycine-substituted (TGA) derivatives and slow decay for the 4-carboxyphenyl-containing one (TPA). Under anaerobic conditions, the direct reduction of these radicals by GSH also occurs with rate constants () from 1.8 × 10 M s for TPA to 1.0 × 10 M s for TGA. Moreover, these radicals can also react with O with rate constants () from 1.2 × 10 M s for ET-01 to 1.6 × 10 M s for TGA. Surprisingly, these radicals are completely inert to Asc in both aerobic and anaerobic conditions. Additionally, the substituents exert an important effect on redox potentials of these trityl radicals. This work demonstrates that the redox properties of the trityl radicals strongly depend on their substituents, and TPA with high stability toward GSH shows great potential for intracellular applications.
四硫代三芳基甲基（三苯甲基）自由基最近被证明可以与生物氧化还原还原剂反应，包括谷胱甘肽 (GSH)、抗坏血酸 (Asc) 和超氧阴离子自由基 (O)。然而，取代基如何影响三苯甲基自由基的反应活性仍不清楚。在这项工作中，合成了五个不对称的三苯甲基自由基，并研究了它们与 GSH、Asc 和 O 的反应性。在有氧条件下，GSH 诱导硫醚取代（TSA）和亚甲基甘氨酸取代（TGA）衍生物快速衰减，而含 4-羧基苯基的衍生物（TPA）则缓慢衰减。在无氧条件下，GSH 也可以直接还原这些自由基，其速率常数 () 从 TPA 的 1.8×10 M s 到 TGA 的 1.0×10 M s。此外，这些自由基还可以与 O 以 1.2×10 M s 的 ET-01 到 1.6×10 M s 的 TGA 的速率常数反应。令人惊讶的是，这些自由基在有氧和无氧条件下对 Asc 完全没有反应。此外，取代基对这些三苯甲基自由基的氧化还原电位有重要影响。这项工作表明，三苯甲基自由基的氧化还原性质强烈依赖于它们的取代基，并且对 GSH 具有高稳定性的 TPA 显示出在细胞内应用的巨大潜力。
