De Novo Psoralens for Photo-Additions to DNA & RNA

补骨脂素是一种草本化合物，具有广泛的治疗和诊断应用。它们可能会插入核糖核酸(DNA和RNA)的碱基对之间，这一过程称为插层作用。在光激发下，插层补骨脂素与碱基胸腺嘧啶或尿嘧啶结合。由此形成的光损伤可能会诱导细胞凋亡。这是PUVA(补骨脂素+UVA辐射)疗法的基础，PUVA疗法治疗某些皮肤病和癌症。在首字母缩写巴黎(补骨脂素分析RNA相互作用和结构)下，光加成也被用于RNA的结构研究。补骨脂素具有较高的插层亲和力和光反应性，将有利于治疗和诊断应用。彼得·吉尔奇的团队率先用时间分辨光谱学对PUVA过程进行了研究。这项工作--部分得到了DFG的支持--揭示了照片添加的机制。研究结果为改进补骨脂素的设计提供了指导。托马斯·穆勒的团队合成了第一代补骨脂素衍生物。它们表现出更高的插层亲和力，但还没有表现出更高的光反应活性。基于这些光谱和合成经验，我们打算在PUVA应用方面进一步改进补骨脂素支架。我们还将转移到更远离这一主题的结构，如倾斜补骨脂素(天使素)和吖啶酮的呋喃衍生物。我们的重点将放在对丹的照片反应性上。根据进展情况，还将考虑与RNA的反应。该项目将受益于光谱学和合成之间的密切合作。它还将得到理论(量子化学和分子动力学)的支持。

Psoralens are herbal compounds with broad therapeutic and diagnostic applications. They may insert themselves between base pairs of ribonucleic acids (DNA and RNA) in a process termed intercalation. Upon photo-excitation intercalated psoralens bind to the bases thymine or uracil. The photo-lesions formed thereby may induce apoptosis of cells. This is the foundation of PUVA (psoralen + UVA-radiation) therapy which treats certain skin diseases and cancers. Under the acronym PARIS (psoralen analysis of RNA interactions and structures), the photo-addition is also utilized for structural studies of RNA. Therapeutic and diagnostic applications would profit from psoralens with higher intercalation affinities and photo-reactivities. Peter Gilch’s group pioneered the investigation of the PUVA process by time-resolved spectroscopy. The effort – in part supported by DFG – revealed the mechanism of the photo-addition. The results provided guidance for the design of improved psoralens. Thomas Müller’s group synthesized a first generation of psoralen derivatives. These exhibited higher intercalation affinities but not yet higher photo-reactivities. Based on these spectroscopic and synthetic experiences, we intend to further improve the psoralen scaffold with respect to PUVA applications. We also will move to structures further apart from this motif like tilted psoralens (angelicins) and furo-derivatives of acridones. Our focus will be the photo-reactivity towards DANN. Depending on the progress also reactions with RNA will be considered. The project will profit from a very close collaboration between spectroscopy and synthesis. It will also receive support from theory (quantum chemistry and molecular dynamics).