De Novo Psoralens for Photo-Additions to DNA & RNA

补骨脂素是具有广泛的治疗和诊断应用的草药化合物。它们可以将自己插入核糖核酸（DNA和RNA）的碱基对之间，这一过程被称为插层。在光激发下，插入的补骨脂素与胸腺嘧啶或尿嘧啶结合。由此形成的光损伤可诱导细胞凋亡。这是治疗某些皮肤病和癌症的PUVA（补骨脂素+ uva辐射）疗法的基础。在首字母缩略词PARIS （psoralen analysis of RNA相互作用和结构）下，光加法也用于RNA的结构研究。具有较高插层亲和力和光反应性的补骨脂素可用于治疗和诊断。彼得·吉尔奇（Peter Gilch）的小组率先用时间分辨光谱学研究了PUVA过程。在DFG的部分支持下，这项工作揭示了光加成的机理。研究结果可为改善补脂素的设计提供指导。Thomas m<e:1> ller的团队合成了第一代补骨脂素衍生物。它们具有较高的插层亲和性，但光反应性还不高。基于这些光谱和合成经验，我们打算进一步改进补骨脂素支架在PUVA方面的应用。我们还将讨论与该基序进一步分离的结构，如倾斜的补骨脂素（angelicins）和吖啶酮的呋喃衍生物。我们的重点将是对DANN的光反应性。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学之间的密切合作。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).