Photocontrolled Binding of Styrylnaphthyridine Ligands to Abasic Site‐Containing DNA by Reversible [2+2] Cycloaddition and Cycloreversion

• Published in: Chemistry : a European journal 2024-06, Vol.30 (31), p.e202400423-n/a
• Main Authors: Schlosser, Julika, Ihmels, Heiko
• Format: Article
• Language: English
• Subjects: Binding; Biological activity; Cycloaddition; Deoxyribonucleic acid; DNA; DNA ligands; DNA recognition; heterocycles; Irradiation; Ligands; photocycloaddition
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202400423

Five novel styrylnaphthyridine derivatives were synthesized and shown to operate as photoswitchable, selective ligands for abasic site‐containing DNA (AP‐DNA), which is an important therapeutic and diagnostic target. These compounds associate with AP‐DNA with binding constants of 0.5–8.4×104 M−1 as shown by photometric and fluorimetric titrations. Specifically, these ligands bind preferentially to AP‐DNA relative to regularly paired duplex DNA. As a special feature, the association of these ligands with DNA can be controlled by means of a reversible [2+2] photocycloaddition. Upon irradiation at 420 nm the photodimer is formed, which does not bind to AP‐DNA. In turn, the naphthyridine is regained with excitation at 315 nm. Most notably, this photoinduced deactivation and release of the DNA ligand can be performed in situ in the presence of AP‐DNA, thus providing a tool for on‐demand delivery of a DNA binder. Overall, these results provide a promising starting point for the development of functional AP‐DNA ligands whose bioactivity can be modulated by light with local and temporal control. Styrylnaphthyridine derivatives are shown to operate as photoswitchable, selective ligands for abasic site‐containing DNA (AP‐DNA). The ligand can be formed from its photodimer in situ in the presence of AP‐DNA, thus providing a promising tool for on‐demand delivery of a DNA binder.