Photoinduced in situ generation of DNA-targeting ligands: Novel approaches towards cytotoxic DNA-binding and DNA-damaging agents

光诱导原位生成 DNA 靶向配体：细胞毒性 DNA 结合剂和 DNA 损伤剂的新方法

• 批准号: 405845168
• 负责人: Professor Dr. Heiko Ihmels
• 金额: --
• 依托单位: Arbeitsgruppe Organische Chemie II
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/405845168?language=en
• 关键词: Photoinduced; situ; generation; DNA; targeting

The interactions between organic ligands and DNA are a paradigm for the identification of lead structures in drug development, because such interactions may affect the physiological functions of the nucleic acid. Indeed, the mode of action of traditional tumor-targeting drugs involves their association or chemical reaction with the DNA of tumor cells. Nevertheless, a major drawback of this chemotherapeutic approach still is the occurrence of severe side effects of the drug on the healthy tissue. These adverse effects may be diminished by drugs that can be applied with spatial and temporal control. For that purpose, chemical compounds are required whose association with DNA can be triggered by an external stimulus. In this research project, we wish to contribute to the quest for time- and space-controllable DNA ligands with the development of photo-generated DNA binders. Based on our previous collaborative work, styrylbenzothiazoles and ortho-styryl-substituted N-heterocycles will be made available that do not bind to DNA. Upon irradiation in the presence of DNA, however, these substrates form cationic hetarenes in situ, which then have a high affinity to DNA. The proposed project is focused on the fundamental investigation of in situ photo-generated DNA ligands with a main emphasis on improved photochemical properties of the substrates, on increased selectivity of the ligands towards particular DNA forms, and on the application of the substrates in vivo.In basic photochemical studies, the influence of the substitution pattern of the styryl substrate on the ligand-forming photoreaction will be examined to identify the optimal structure of the chromophore with regard to solubility, bio-compatibility of the absorption properties, photoreactivity, reluctance of the substrate to bind to DNA, and affinity of the resulting photoproduct to the nucleic acid. In addition, structure variations will be tested that shall enable higher affinity to the DNA by the formation of bis-intercalators, or that accomplish selective binding of the in situ formed ligand to irregular or non-canonical DNA forms, such as quadruplex DNA or abasic site-containing DNA. The latter nucleic-acid structures play essential roles in biologically relevant processes, so that photo-controllable ligands which bind to them are attractive targets in drug design. Another sub-project aims at the synthesis of styryl substrates that are attached to a DNA-damaging functionality, which enables the chemical modification of DNA, i.e. a more sustaining change of the DNA structure and activity. According to the main principle, only after the photoinduced formation of the DNA intercalator the DNA-damaging functionality is efficiently delivered into the close vicinity of DNA, where it can subsequently induce the formation of DNA lesions. Finally, the cytotoxicity of the substrates and photoproducts will be tested in cells to assess the general approach in vivo.

有机配体和DNA之间的相互作用是药物开发中鉴定先导结构的范例，因为这种相互作用可能影响核酸的生理功能。事实上，传统肿瘤靶向药物的作用模式涉及它们与肿瘤细胞DNA的缔合或化学反应。然而，这种化疗方法的主要缺点仍然是药物对健康组织的严重副作用的发生。这些副作用可以通过可以在空间和时间控制下应用的药物来减少。为此，需要化学化合物，其与DNA的结合可以由外部刺激触发。在本研究项目中，我们希望通过开发光生DNA结合剂，为寻求时间和空间可控的DNA配体做出贡献。基于我们以前的合作工作，苯乙烯基苯并噻唑和邻-苯乙烯基取代的N-杂环将不与DNA结合。然而，在DNA存在下照射时，这些底物原位形成阳离子杂烯，其然后对DNA具有高亲和力。该项目的重点是原位光生DNA配体的基础研究，主要侧重于改进底物的光化学性质，提高配体对特定DNA形式的选择性，以及底物在体内的应用。苯乙烯基底物的取代模式对配体的影响-将检查形成光反应以确定发色团在溶解性、吸收性质的生物相容性、光反应性、底物与DNA结合的阻力以及所得光产物对核酸的亲和力。此外，将测试结构变化，其通过形成双嵌入剂而能够实现对DNA的更高亲和力，或者实现原位形成的配体与不规则或非规范DNA形式（例如四链体DNA或含脱碱基位点的DNA）的选择性结合。后者的核酸结构在生物学相关过程中起着重要作用，因此与它们结合的光可控配体在药物设计中是有吸引力的靶标。另一个子项目旨在合成与DNA损伤功能性连接的苯乙烯基底物，这使得能够对DNA进行化学修饰，即DNA结构和活性的更持久的变化。根据主要原理，只有在DNA嵌入剂光诱导形成后，DNA损伤功能才能有效地传递到DNA附近，随后可以诱导DNA损伤的形成。最后，将在细胞中测试底物和光产物的细胞毒性，以评估体内的一般方法。