Novel triazole and morpholine substituted bisnaphthalimide: Synthesis, photophysical and G-quadruplex binding properties

Abstract

Four bisnaphthalimides derivatives 3a, 3b, 5a and 5b with polyamine linkage have been synthesized and characterized. Different spectroscopic techniques, including UV–Vis spectroscopy, fluorescence spectroscopy, circular dichroism and fluorescence resonance energy transfer (FRET), have been used to explore the interaction of these compounds with G-quadruplex structures (Htelo, c-myc, c-kit). The compounds 3a, 3b and 5b show high affinity toward Htelo, c-myc and c-kit G-quadruplexes (Ka > 4.42 × 106 M−1), and exhibit more than 40-fold selectivity for the quadruplex versus CT DNA. Binding of 3a, 3b to telomeric and oncogenic G-quadruplexes induce strong enhancement of the fluorescence intensity (18–27-fold), whereas the duplex CT DNA induces much weaker fluorescence enhancement (around 2-fold). Being fluorescent, the cellular localization of 3a, 3b can be conveniently tracked by fluorescence imaging. The results indicate that 3a, 3b can readily be taken up by A549 lung cancer cells. Molecular docking studies indicate that 3a, 3b, 5a and 5b mainly bind in the groove and/or loop region of the G-quadruplexes, and hydrogen bonding plays an important role in the interaction of bisnaphthalimide derivatives with G-quadruplexes. CD spectroscopy and FRET melting assay indicate that 3a, 3b and 5b can promote the formation and the stabilization of human telomeric and c-myc G-quadruplex DNA. The compound 3b can inhibit the growth of A549 cells (IC50 = 0.15 μM), with a much higher antitumor activity than amonafide.