N,N′,N′′-Trisubstituted guanidine derivatives as DNA-intercalators: synthesis, crystal structures and biophysical investigations

Abstract

Three new N,N′,N′′-trisubstituted guanidine derivatives (L1, L2 and L3) were synthesized and characterized using NMR and mass spectral studies. The structures of these ligands have been confirmed using single-crystal XRD studies. The interactions between these ligands and calf-thymus DNA (CT-DNA) were investigated in vitro using different spectroscopic methods and molecular docking and simulation methods in a physiological buffer (pH 7.4). UV-Vis spectral titrations suggested the formation of an L2/CT-DNA complex. The addition of increasing amounts of CT-DNA enhanced the fluorescence of L2 with a binding constant on the order of 10⁴ M⁻¹, indicating fairly strong binding between them. Thermodynamic parameters ΔG⁰ < 0 and |ΔH⁰| < T|ΔS⁰| suggested that the complexation is spontaneous and entropy-driven where hydrophobic interaction plays a dominant role in stabilizing the complex. Molecular docking and metadynamics simulation studies indicated partial intercalation of one of the phenyl rings between the base pairs of DNA, which is strongly supported by circular dichroism, viscosity measurements and KI quenching studies.