Core-extended Naphthalene Diimide dyads as light-up probes with targeted cytotoxicity toward tumor cells

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