Core-Extended Naphthalene Diimide Dyads as Light-Up Probes with Targeted Cytotoxicity Toward Tumor Cells

Within the framework of rational drug design, this study introduces a novel approach to enhance the specificity of small molecules in targeting cancer cells. This approach starts from the use of dyads merging into a single entity, a naphthalene diimide (NDI) and core-extended NDI (ceNDI), both known as G-quadruplex (G4) ligands and fluorescent probes. The strategy aims to leverage the unique diagnostic strengths of the ceNDI moiety featuring red emission by improving its binding affinity and target selectivity through inclusion in dyads built with different linkers. The newly developed NDI-ceNDI dyads are promising probes, as they exhibit fluorescence turn-on upon DNA recognition and induced circular dichroism signals dependent on DNA conformation. Both dyads have an excellent affinity for hybrid G4, with two orders of magnitude higher binding constants than those for ds DNA. Their high cytotoxicity on cancer cell lines further demonstrates their potential as therapeutic agents, highlighting the role of the linker in target selectivity. Specifically, only the dyad with the rigid triazole linker exhibits selectively induced DNA damage in transformed cells, compared to normal cells primarily targeting telomeric regions. Our findings shed light on DIPAC’s potential as a promising theranostic agent, offering insights into future developments in precision medicine.