Importance of the hydroxyl substituents in the B–ring of plant flavonols on their preferential binding interactions with VEGF G–quadruplex DNA: Multi-spectroscopic and molecular modeling studies

Abstract G-quadruplex (G4) structures are known to be promising anticancer drug targets and flavonols (an important class of flavonoids) are small molecules reported to possess several health–promoting properties including those of anticancer activities. In this work, we explored the interactions of the structurally related plant flavonols kaempferol (KAE; 3,5,7,4′ OH flavone) and morin (MOR; 3,5,7,2′,4′ OH flavone) with various G4–DNA sequences along with duplex DNA using a combination of spectroscopic and molecular docking studies. Our results revealed that KAE shows preferential interaction with VEGF G4–DNA in comparison to the other G4 sequences and duplex DNA. Moreover, KAE enhances the thermal stability of VEGF G4–DNA. In contrast, MOR exhibits an appreciably weaker level of interaction with both duplex and various G4–DNAs, with no significant structural specificity. The contrasting DNA binding behaviors suggest a crucial role of the 2′ OH substituent in the B–ring of flavonol moiety. While KAE is relatively planar, MOR adopts a significantly non–planar conformation attributable to steric hindrance from the additional 2′ OH substituent. This small structural difference is apparently very important for the ability of KAE and MOR to interact with VEGF G4–DNA. Thus, KAE (but not MOR) appears to be an effective ligand for VEGF G4–DNA, opening up possibilities of its application for regulation of gene expression in cancer cells.