Carbazole derivative as an effective telomeric G-quadruplex DNA binder

Telomeric DNA acts as mitotic clock being gradually reduced at each cell division cycle, which will lead the cell to senescence and apoptosis. The G-rich sequences at telomeres can adopt G-quadruplex structures, which have been shown to directly inhibit the enzyme telomerase. The rational design of small-molecule ligands, with a particular focus on the structural features required for selectively binding to G-quadruplex structures, is significant and useful in biochemistry and clinical diagnosis. Here, a new small-molecule ligand Cp-1, a carbazole-quinolinum core bridged with a phenylboronic acid side chain, has been synthesized and characterized by NMR spectroscopy and mass spectrometry. The binding affinity and selectivity towards telomeric G-quadruplex DNA have been determined by fluorescence spectroscopy, UV/Vis titrations, CD spectroscopy and molecular docking study. These studies have shown that the ligand Cp-1 has higher binding affinity and selectivity towards telomeric G-quadruplex over duplex DNA. Binding mode analysis indicated Cp-1 interacted with G-quadruplex DNA mainly through end-stacking mode. Further, the ligand could enter live cells and localize in the cytoplasm as shown by confocal fluorescence microscopy. (C) 2021 Elsevier Ltd. All rights reserved.