Visualization of Parallel G-Quadruplexes in Cells with a Series of New Developed Bis(4-aminobenzylidene)acetone Derivatives

[Image: see text] G-quadruplexes (G4s) are unique four-stranded nucleic acid secondary structures formed by G-rich nucleic acid sequences which are prevalent in gene promoter and telomere regions and deemed to play essential roles in many biological and pathological processes. Although attentions to G4s have been paid for nearly 40 years, G4 selectivity and its topology discrimination in cells is still pending. Small fluorescence molecules are emerging as a versatile tool of interrogation of cellular features in vivo. Herein, a new class of bis(4-aminobenzylidene)acetone derivatives GD1, GD2, and GD3 with excellent environment-sensitive emission properties were developed and used for fluorescent detection of G4s. Among them, compound GD3 owning four methoxy groups presented preferable capability of lighting up parallel G4s with a strong red-emission enhancement. The photophysical property of GD3 was systematically investigated to elucidate the turn-on mechanism of GD3 toward parallel G4 structures, which reveal that the binding-induced polarity change of the microenvironment around GD3 together with the fluorophore conformational confinement affected the molecular intramolecular charge-transfer state and resulted the enhanced emission. G4s staining with GD3 in fixed cells was further applied, demonstrating GD3 a promising probe with the ability to visualize the distribution of G4 structures in biological processes. In general, this study provides a new potential scaffold—bis(4-aminobenzylidene)acetone—for design of G4-selective fluorescence probes.