De Novo Psoralens for Photo-Additions to DNA & RNA

De Novo Psoralens 用于 DNA 光添加

• 批准号: 318058865
• 负责人: Professor Dr. Peter Gilch
• 金额: --
• 依托单位: Arbeitsgruppe Femtosekundenspektroskopie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/318058865?language=en
• 关键词: De; Novo; Psoralens; Photo; Additions

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).

补骨脂素是一种具有广泛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，这一过程称为插入。在光激发时，插入的peptiens与碱基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PUVA（peptide + UVA-辐射）疗法的基础，可治疗某些皮肤疾病和癌症。在首字母缩写巴黎（RNA相互作用和结构的peptien分析）下，光加成也用于RNA的结构研究。治疗和诊断应用将受益于具有更高的嵌入亲和力和光反应性的绿脓杆菌。Peter Gilch的团队率先通过时间分辨光谱学研究PUVA过程。这项努力-部分得到DFG的支持-揭示了光加成的机制。研究结果为改进型pneumens的设计提供了指导。托马斯·穆勒的小组合成了第一代的补骨脂素衍生物。这些表现出较高的插层亲和力，但还没有更高的光反应性。基于这些光谱和合成的经验，我们打算进一步改善peptiben支架相对于PUVA应用。我们也将进一步转移到结构远离这一主题，如倾斜peptides（当归素）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，也将考虑与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。