Instituto Universitario Mixto de Tecnología Química (UPV-CSIC), Universitat Politècnica de València, Consejo Superior de Investigaciones Científicas, 46022 Valencia, Spain.
Instituto de Ciencia Molecular, Universitat de València, P.O.Box 22085, 46071 València, Spain.
J Org Chem. 2023 Jul 21;88(14):10111-10121. doi: 10.1021/acs.joc.3c00930. Epub 2023 Jul 12.
The quest for simple systems achieving the photoreductive splitting of four-membered ring compounds is a matter of interest not only in organic chemistry but also in biochemistry to mimic the activity of DNA photorepair enzymes. In this context, 8-oxoguanine, the main oxidatively generated lesion of guanine, has been shown to act as an intrinsic photoreductant by transferring an electron to bipyrimidine lesions and provoking their cycloreversion. But, in spite of appropriate photoredox properties, the capacity of guanine to repair cyclobutane pyrimidine dimer is not clearly established. Here, dyads containing the cyclobutane thymine dimer and guanine or 8-oxoguanine are synthesized, and their photoreactivities are compared. In both cases, the splitting of the ring takes place, leading to the formation of thymine, with a quantum yield 3.5 times lower than that for the guanine derivative. This result is in agreement with the more favored thermodynamics determined for the oxidized lesion. In addition, quantum chemistry calculations and molecular dynamics simulations are carried out to rationalize the crucial aspects of the overall cyclobutane thymine dimer photoreductive repair triggered by the nucleobase and its main lesion.
寻求实现四元环化合物光还原裂解的简单体系不仅是有机化学，而且也是模拟 DNA 光修复酶活性的生物化学领域的一个关注点。在这种情况下，8-氧鸟嘌呤已被证明是一种内在的光还原剂，可通过将电子转移到嘧啶二聚体损伤部位并引发其环化重排来发挥作用。但是，尽管具有适当的光氧化还原特性，但鸟嘌呤修复环丁烷嘧啶二聚体的能力尚不清楚。在这里，合成了含有环丁烷胸腺嘧啶二聚体和鸟嘌呤或 8-氧鸟嘌呤的二聚体，并比较了它们的光反应活性。在这两种情况下，环都发生了裂解，生成了胸腺嘧啶，其量子产率比鸟嘌呤衍生物低 3.5 倍。这一结果与氧化损伤所确定的更有利的热力学相一致。此外，还进行了量子化学计算和分子动力学模拟，以合理化由碱基及其主要损伤触发的整个环丁烷胸腺嘧啶二聚体光还原修复的关键方面。
