Microenvironment‐Sensitive Fluorescent Ligand Binds Ascaris Telomere Antiparallel G‐Quadruplex DNA with Blue‐Shift and Enhanced Emission

The development of small molecules that can selectively target G‐quadruplex (G4) DNAs has drawn considerable attention due to their unique physiological and pathological functions. However, only a few molecules have been found to selectively bind a particular G4 DNA structure. We have developed a fluorescence ligand Q1, a molecular scaffold with a carbazole–pyridine core bridged by a phenylboronic acid side chain, that acts as a selective ascaris telomere antiparallel G4 DNA ASC20 ligand with about 18 nm blue‐shifted and enhanced fluorescence intensity. Photophysical properties revealed that Q1 was sensitive to the microenvironment and gave the best selectivity to ASC20 with an equilibrium binding constant Ka=6.04×105 M−1. Time‐resolved fluorescence studies also demonstrated that Q1 showed a longer fluorescence lifetime in the presence of ASC20. The binding characteristics of Q1 with ASC20 were shown in detail in a fluorescent intercalator displacement (FID) assay, a 2‐Ap titration experiment and by molecular docking. Ligand Q1 could adopt an appropriate pose at terminal G‐quartets of ASC20 through multiple interactions including π–π stacking between aromatic rings; this led to strong fluorescence enhancement. In addition, a co‐staining image showed that Q1 is mainly distributed in the cytoplasm. Accordingly, this work provides insights for the development of ligands that selectively targeting a specific G4 DNA structure. Selective G4 DNA ligands: We report a novel microenvironment‐sensitive fluorescent ligand (Q1) that shows selectivity to ascaris telomere antiparallel G4 DNA ASC20 through enhanced fluorescence intensity along with about 18 nm blue‐shifted properties. The detailed interactions of Q1 with ASC20 G4 DNA are illustrated, and the results demonstrate that Q1 mainly binds at the terminals of ASC20 through an end‐stacking mode.