Conjugating a groove binder analogue to a styryl-quinolinium scaffold for the light-up detection of duplex and G-Quadruplex DNA with different binding modes.

Abstract

The rational design of novel small molecules, which can target specific DNA sequences or secondary structural DNAs, is one of the most important goals in medicinal chemistry. Also the studies of DNA binding potency which can give fundamental insight into binding mechanisms and specificity are essential. In this paper, a N-methylated quinolinium probe NSQ functionalized with a G-Quadruplex DNA groove binder analogue was designed and synthesized. NSQ was found to express selective and sensitive for "light-up" detection of both G-Quadruplex and duplex DNAs over RNA and other biomolecules. The characteristics of NSQ and its interactions with DNAs were comprehensively evaluated by means of fluorescence, UV-Vis, circular dichroism, FID assay, DFT calculation and molecular docking. NSQ exhibited higher binding affinity to G-Quadruplex than to duplex DNA. Binding mechanism analysis indicated NSQ interacted with G-Quadruplex DNA mainly through end-stacking mode, while bound with duplex DNA into the minor groove of AT-rich regions. Further, NSQ exhibited potent invitro anti-tumor activity, and to elucidate the cellular applications, confocal cell imaging was carried out and validated its mainly nuclear localization.