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

点击翻译按钮获取中文摘要

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.