Designed NIR-I Emissive and Selective G-Quadruplex DNA Binder with Altered Organelle Specificity

Abstract

In this work, we report the discovery of a G-quadruplex DNA-selective and near-infrared (NIR-I) emissive G-quadruplex binder derived from a known styryl-quinolinium-based compound. This molecule is unique in its class, with an emission wavelength above 800 nm, and displays selective G-quadruplex binding. Among the synthesized molecules, compound 2 emerged as a selective and the best G-quadruplex binder through comparative studies and exhibited strong thermal stabilization on Pu22 G-quadruplex with a ΔTm of 21.7 °C (at a 1:3 DNA to ligand ratio). G-quadruplex DNA-binding studies showed that thermal stabilization was topology-dependent. CD, UV–vis, and docking studies were performed to confirm the binding of these compounds to the different G-quadruplexes. Solution NMR studies confirmed the binding of compound 2 to the Pu22 G-quadruplex DNA. Cell-based studies showed that compound 2 was significantly cytotoxic to MCF-7 cancer cells and was readily taken up by the cells. However, cell internalization studies showed contrasting changes in the internalization properties, with compound 2 displaying a significant population on the nuclear periphery, which was altogether different from its parent compound 1, which did not show such changes.