Synthesis, G-quadruplex binding properties and cytotoxicity of naphthalimide-thiourea conjugates

Four novel naphthalimide-thiourea conjugates 3a-d have been prepared and characterized. The interactions of these compounds with duplex and telomeric G-quadruplex DNA have been investigated by UV-Vis spectroscopy, fluorescence spectroscopy, viscosity and cyclic voltammetric measurements. The studies reveal that 3a-d possess high affinity (>1.20 x 10(7) M-1) and reasonable selectivity for telomeric G-quadruplex DNA over duplex DNA. Viscosity and cyclic voltammetric experiments suggest that 3a-d bind to duplex DNA through a classical intercalation mode. Molecular docking studies indicate that 3a-d associate with telomeric G-quadruplexes through groove binding, and hydrogen bonding interactions exist between the thiourea moiety and the phosphates or the bases in the G-quadruplex. The emissive nature of compounds 3a-d makes it possible to study their localization in A549 cells by fluorescence microscopy. The representative compounds 3d and 3b are mainly localized in the nuclei after 4 h of incubation. All four compounds inhibit A549 cells selectively over normal HUVEC cells, with a higher antitumor activity than amonafide.