Beyond telomeric G-quadruplexes: remarkable binding of <bold/> to promoter sequences

Due to their key roles in tumor growth and carcinogenesis, G-quadruplexes have been established as potential drug targets for the treatment of cancer. Small molecules that are capable of binding and stabilizing G-quadruplexes present an important strategy for developing new cancer therapeutics. Phenanthroline cores containing planar aromatic rings and the capability to have pi-interactions are known to preferentially bind with the G-quadruplexes over duplexes. One such compound is PhenQE8, which is known for its excellent anticancer properties and non-cytotoxicity to normal cells. Previously, its binding study was limited to a human telomeric G-quadruplex sequence only. In this work, we expand the binding repertoire of PhenQE8 to non-telomeric sequences and report that it far supersedes its thermal stabilization to promoter G-quadruplexes when compared to the human telomeric G-quadruplex. A CD-based thermal denaturation experiment showed that PhenQE8 had high selectivity towards the G-quadruplexes over duplex DNA, with a strong thermal stabilization of Pu22 G-quadruplex DNA (Delta Tm = 28.1 degrees C). Further CD spectroscopic studies revealed that PhenQE8 interacted with the Pu22 G-quadruplex DNA through the stacking mode of binding, which was further supplemented by the molecular docking studies. These results offer new insights into the anticancer activity of PhenQE8, which may be linked to its strong binding to promoter G-quadruplexes in addition to its known binding to the human telomeric G-quadruplex DNA.