Thermodynamics and kinetic studies in the binding interaction of cyclic naphthalene diimide derivatives with double stranded DNAs.

Previously, we reported our investigations of the interaction between a cyclic naphthalene diimide derivative (cNDI 1 ) and double stranded DNA (dsDNA) ( Bioorg. Med. Chem. 2014 , 22 , 2593). Here, we report the synthesis of the novel cNDI 2 , which has shorter linker chains than cNDI 1 . We performed comparative investigations of the interactions of both cNDI 1 and cNDI 2 with different types of dsDNA, including analysis of their thermodynamics and kinetics. Interactions between the cNDIs and calf thymus DNA (CT-DNA), poly[d(A-T)] 2 , or poly[d(G-C)] 2 were explored by physicochemical and biochemical methods, including UV–Vis spectroscopy, circular dichroism (CD) spectroscopy, stopped-flow kinetics, and a topoisomerase I assay. Upon addition of cNDIs to CT-DNA, the existence of an induced CD signal at approximately the wavelength of the naphthalene diimide chromophore and unwinding of the DNA duplex, as detected by the topoisomerase I assay, revealed that cNDIs bound to the DNA duplex. As indicated by the steric constraint in the formation of the complex, bis-threading intercalation was the more favorable binding mode. UV–Vis spectroscopic titration of the cNDIs with DNA duplexes showed affinities on the order of 10 5 –10 6 M −1 , with a stoichiometry of one cNDI molecule per four DNA base pairs. Thermodynamic parameters (Δ G , Δ H , and Δ S ) based on the van’t Hoff equation indicated that exothermic and entropy-dependent hydrophobic interactions played a major role in the reaction. Stopped-flow association and dissociation analysis showed that cNDI interactions with poly[d(G-C)] 2 were more stable and had a slower dissociation rate than their interactions with poly[d(A-T)] 2 and CT-DNA. Measurement of ionic strength indicated that electrostatic attraction is also an important component of the interaction between cNDIs and CT-DNA. Because of its longer linker chain, cNDI 1 showed higher binding selectivity, a more entropically favorable interaction, and much slower dissociation from dsDNA than cNDI 2 . [ABSTRACT FROM AUTHOR]