Selective recognition of specific G-quadruplex vs. duplex DNA by a phenanthroline derivative

A key problem in designing G-quadruplex ligand is how to discriminate quadruplex DNA specifically from other DNAs, searching ligands targeted at special G-quadruplex structure with high selectivity is a major challenge. Herein, a phenanthrolin-dicarboxylate ester (PD) is proved to exhibit selectivity toward parallel and hybrid G-quadruplex structures with propeller and edge-wise loops, over duplex DNA and antiparallel quadruplex structure with diagonal loop. Such preferred binding of PD to these special G-quadruplex structures is possibly resulted from steric hindrance of: (1) the four substituent groups in PD molecule which prevent close interaction with duplex DNA and (2) the diagonal loop above the G-tetrads in antiparallel G-quadruplex which hinder face-to-face stacking of planar phenanthrolin ring to G-tetrads. In line with its stabilizing ability of G-quadruplex, PD molecule exhibit a inhibitory ability telomerase activity, as well as the potent cytotoxic activity against several human cancer cell lines, which makes it an interesting anti-tumor drug lead.