Development of a near-infrared fluorescent ligand that visualizes and stabilizes G-quadruplexes by decorating the triphenylamine scaffold

Abstract

Abstract G-quadruplex (G4) structures are often enriched in cancer-driving genes with elevated transcriptional activity, which are now treated as potential targets for cancer diagnosis and therapy. Thus, development of dual-function ligands that can simultaneously visualize and stabilize G4s are urgently needed. In this study, two π-extended compounds were designed and synthesized by decorating the triphenylamine scaffold with positively charged indolium moieties, which were then revealed as NIR fluorescent probes possessing AIE characteristics. Next, the more promising compound TAIN-2 was further investigated, demonstrating that TAIN-2 could selectively bind to G4s through an end-stacking mode, which thereby triggered its fluorescence by restricting the intramolecular rotations, and largely stabilized the G4 structures. Finally, we also explored the applications of TAIN-2 in the triple-negative breast cancer (TNBC) cells, and the results suggested that TAIN-2 may have the ability to visualize and stabilize the intracellular G4s, holding great potential to develop into feasible diagnostic/therapeutic dual-function agents for TNBC. This study provides new insights into the development of novel theranostic agents for cancers.