Pyrimidine dimerization is the dominant DNA photoreaction occurring in vitro and in vivo. Three types of dimers, cyclobutane pyrimidine dimers (CPDs), pyrimidine (6-4) pyrimidone photoproducts (6-4PPs), and the spore photoproduct (SP), are formed from the direct dimerization process; it is of significance to understand the photochemistry and photobiology of these dimers. Traditionally, pyrimidine dimerization was studied by using the natural pyrimidine residues thymine and cytosine, which share similar chemical structures and similar reactivity, making it sometimes less straightforward for one to identify the key pyrimidine residue that needs to be excited to trigger the photoreaction. We thus adopted synthetic chemistry to selectively modify the pyrimidine residues or to introduce pyrimidine analogs to the selected positions before UV irradiation is applied. By monitoring the subsequent outcomes from the photoreaction, we were able to gain unique mechanistic insights into the photochemistry of SP as well as of CPDs and 6-4PPs. Moreover, our approaches have resulted in several useful “tools” that can facilitate the understanding of lesion photobiology. Our results summarized in this account illustrate what organic synthesis/chemical analysis may allow us to achieve in future DNA lesion biology studies. 1 Introduction 2 Using the Deuterium Labeling Strategy to Understand SP Formation 3 Using Microcrystals to Reveal the Reaction Intermediates in SP Formation 4 Using a Phosphate Isostere to Understand the SP Structure 5 Synthesis of SP Phosphoramidite and SP Structural Studies 6 Using a Thymine Isostere to Understand CPD Formation 7 Using a Thymine Isostere to Understand 6-4PP Photoreaction 8 Understanding the Chemical Stability of SP 9 Understanding the Chemical Stability of 6-4PP 10 Summary and Perspectives for Future Research

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利用有机合成和化学分析了解孢子光产物和其他嘧啶二聚体的光化学

嘧啶二聚化是体外和体内发生的主要 DNA 光反应。由直接二聚过程形成三种类型的二聚体，环丁烷嘧啶二聚体（CPDs）、嘧啶（6-4）嘧啶酮光产物（6-4PPs）和孢子光产物（SP）；了解这些二聚体的光化学和光生物学具有重要意义。传统上，嘧啶二聚化是通过使用天然嘧啶残基胸腺嘧啶和胞嘧啶来研究的，它们具有相似的化学结构和相似的反应性，因此有时很难确定需要激发以触发光反应的关键嘧啶残基。因此，我们采用合成化学来选择性地修饰嘧啶残基或在应用紫外线照射之前将嘧啶类似物引入选定的位置。通过监测光反应的后续结果，我们能够对 SP 以及 CPD 和 6-4PP 的光化学获得独特的机械见解。此外，我们的方法产生了几种有用的“工具”，可以促进对病变光生物学的理解。我们在这个帐户中总结的结果说明了有机合成/化学分析可以让我们在未来的 DNA 损伤生物学研究中实现什么。