Disubstituted quinazoline derivatives as a new type of highly selective ligands for telomeric G-quadruplex DNA

A series of 2,4-disubstituted quinazoline derivatives found to be a new type of highly selective ligand to bind with telomeric G-quadruplex DNA, and their biological properties were reported for the first time.Their interactions with telomeric G-quadruplex DNA were evaluated by using fluorescence resonance energy transfer (FRET) melting assay, circular dichroism (CD) spectroscopy, surface plasmon resonance (SPR), nuclear magnetic resonance (NMR), and molecular modeling. Our results showed that these derivatives could well recognize G-quadruplex and have high selectivity toward G-quadruplex over duplex DNA. The structure–activity relationships (SARs) study revealed that the disubstitution of quinazoline and the length of the amide side chain were important for its interaction with the G-quadruplex. Furthermore, telomerase inhibition of the quinazoline derivatives and their cellular effects were studied.

A series of quinazoline derivatives as novel telomeric G-quadruplex ligands were synthesized and evaluated. These derivatives could well recognize G-quadruplex DNA and have significant cellular biological activity.Figure optionsDownload as PowerPoint slideHighlights
► 17 quinazoline derivatives as novel G-quadruplex DNA ligands were synthesized.
► They showed high binding affinity and selectivity with telomeric G-quadruplex DNA.
► 11d could significantly inhibit cellular biological activity.