Pyrazine-based G-quadruplex fluorescent probes: Transformation between aggregation-induced emission and disaggregation-induced emission via slight variations in structures

Abstract

G-quadruplexes (G4s) play key regulatory roles in biological processes, holding great potential as novel therapeutic targets. Fluorescent probes may help elucidate the structure-function relationships of G4s in biological systems, providing useful information for drug development. However, G4 probes through rational design are still limited, and the rationales of G4 probes are not well explored, which hinders the development of new G4 probes. In this work, we carried out a proof-of-concept study. Two pyrazine-based G4 fluorescent probes (PZ-1 and PZ-2) based on the AIE or DIE principles were first designed. Then, their fluorescence-triggering mechanisms upon binding to G4s were thoroughly investigated, demonstrating that slight variations in structures would result in transformation between AIE and DIE regarding these two probes. Next, the DIE probe PZ-2 was selected for further studies, which was demonstrated to be able to selectively sense kinds of G4s. Furthermore, the binding modes between PZ-2 and G4s were explored, revealing that G4s could dissociate PZ-2 aggregate and then accommodate its monomer through an end-stacking mode, thus triggering its fluorescence. Accordingly, this work provides new insights for the rational design of G4 fluorescent probes.