Photoinduced in situ generation of DNA-targeting ligands: Novel approaches towards cytotoxic DNA-binding and DNA-damaging agents
Final Report Abstract
In this project, approaches towards the photochemical activation of DNA ligands were investigated in order to develop new insights and methods that can be used in the long term to limit the side effects of DNA-targeting cytotoxic agents. For this purpose, various styrylsubstituted aromatic heterocycles were synthesized, that do not bind to DNA, but can be converted into DNA-binding ligands upon irradiation. For example, the photoreactions of selected (3,4-dimethoxystyryl)pyridines with different substituents at the pyridine unit led to quinolizinium derivatives that intercalate into DNA. This reaction cascade can be induced directly in the presence of DNA. In addition, these intercalators were also used as photosensitizers that induce DNA-strand breaks through the formation of hydroxyl radicals and reactive secondary intermediates under anaerobic conditions. In a variation of this approach, for the first time photogenerated DNA ligands were made available that selectively bind to DNA with abasic positions (AP DNA), i.e., a non-regular DNA which is an important therapeutic target in drug discovery. For this purpose, the styrylpyridine was attached with bulky substituents, so that DNA intercalation is sterically hindered, whereas this compound can still be accommodated in the binding site of AP-DNA. This AP-DNA/ligand complex was also formed when the styrylpridine was irradiated in the presence of the DNA. The concept was extended to styrylnaphthyridines which preferentially bind to AP-DNA based on specific hydrogen bonds and whose DNA-binding properties can be reversibly activated and deactivated upon irradiation. Irradiation in the presence of DNA deactivated these compounds in a [2+2] photocycloaddition because the photodimers no longer bind to the AP DNA. The ligands, in turn, were recovered in situ by irradiation at another wavelength in a cycloreversion. For the first time, an efficient, generally applicable method for the targeted, controlled activation and deactivation of a selective AP-DNA ligand was presented. Overall, the results provide helpful starting points for the further development of functional, selective DNA ligands, whose activity can be modulated locally and temporally by light irradiation.
Publications
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Ligands for Abasic Site-containing DNA and their Use as Fluorescent Probes. Current Organic Synthesis, 20(1), 96–113.
Ihmels, Heiko & Schlosser, Julika
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Photoinduced Reactions of Styrylpyridine Derivatives for the In Situ Formation of Selective Ligands for Apyrimidinic DNA. ChemPhotoChem, 7(12).
Schlosser, Julika; Stötzel, Nils; Fedorov, Yuri & Ihmels, Heiko
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Selective Fluorimetric Detection of Pyrimidine Nucleotides in Neutral Aqueous Solution with a Styrylpyridine-Based Cyclophane. Chemistry, 5(2), 1220-1232.
Schlosser, Julika; Hebborn, Julian F. M.; Berdnikova, Daria V. & Ihmels, Heiko
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Photocontrolled Binding of Styrylnaphthyridine Ligands to Abasic Site‐Containing DNA by Reversible [2+2] Cycloaddition and Cycloreversion. Chemistry – A European Journal, 30(31).
Schlosser, Julika & Ihmels, Heiko
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Photoinduced in situ generation of DNA-targeting ligands: DNA-binding and DNA-photodamaging properties of benzo[c]quinolizinium ions. Beilstein Journal of Organic Chemistry, 20, 101-117.
Schlosser, Julika; Fedorova, Olga; Fedorov, Yuri & Ihmels, Heiko
