Interaction Of 2-Aryl Benzimidazole Derivatives And Its Rare Earth Complexes With Calf Thymus DNA

DNA is the carrier of genetic information in almost all organisms, which is regulating the reproduction, growth and death or other vital activities. Modern medicine has confirmed that DNA is the primary site of action of many drug molecules. Studying interaction between drug molecules and DNA, it not only could provide the mechanism of drug molecules interaction with DNA from the molecular level, but also offer some theoretical guidance for the design and optimization of the molecular structure of the drug. This research has become an important part in many areas such as molecular biology, medicinal chemistry and clinical medicine.Benzimidazole is a well known famous structure that a benzene ring is fused with an imidazole. Its derivatives and metal complexs are widely used in anti-viral,anti-fungal, anti-oxidation, anti-tumor, treatment of physiological disorders and simulation of metal enzymes, etc. Recent years, with the deepening of research on benzimidazole, researchers found that the introduction of an aromatic group at C-2position or with rare earth ions to form metal complex can to some extent enhance or change its pharmacologically active. Based on relevant literature, in this paper, a series of benzimidazole derivative compounds and a rare earth metal lanthanum benzimidazole-coordination compound are synthesized and characterized by 1H NMR,12 C NMR and elemental analysis,etc. Meanwhile, the interaction of them with calf thymus DNA(ct-DNA) have been intevestigated by using kinds of spectroscopy,hydromechanics and molecular docking. The present work consists of the following several parts:In the first part, three kinds of benzimidazole derivative compounds having the different substituent group and position were synthesized and characterized by 1H NMR,12 C NMR, fourier transform infrared spectrum(FT-IR), elemental analysis and mass spectrometry.In the second part, the interaction between 2-{3’-[2’’-(N,N-diisopropyl)]ethoxy}phenyl-1H-benzimidazole(DEPBI) and ct-DNA under physiological conditions was studied by using a variety of methods, which including UV-vis absorbance,fluorescence and resonance light scattering spectrum(RLS), melting, viscosity, ionic strength and molecular docking method. UV-vis experiments shown that after addingvarious concentrations of ct-DNA, the DEPBI absorption bands occured hypochromicity and blue shift effect, which inferred that the interaction between ct-DNA and DEPBI was a non-classical intercalation. The mode of interaction between them via melting point and viscosity experiments were further verified by non-classical intercalation(partial insertion). Moreover, the ionic strength experimental result proved that there was still some of the electrostatic interaction.According to Stern-Volmer and double logarithmic equation: it revealed that the quenching mechanism of DEPBI by ct-DNA was mainly static quenching procedure;under three different temperatures(298,304,310K), the binding constants Ka were calculated 5.83,4.31,1.27 × 104 L/mol, respectively. The thermodynamic parametersΔH(-91.86 KJ·mol-1), ΔS(-44.60 J·mol-1·K-1) and ΔG(-19.20 KJ·mol-1) were calculated by thermodynamic equation, and it could be inferred that the action forces were mainly van der Waals force and hydrogen bonds. RLS spectrum shown that 2-aryl benzimidazole ring of a planar structure of DEPBI inserted into the base pairs of ct-DNA, forming π ~ π*stack and aggregating into large particles scatterer. At the same time, the molecular docking result simulated that the position of 2-aryl benzimidazole ring inserted into the ct-DNA base pair and the length of hydrogen bond.In the third part: a novel and three-dimensional lanthanide coordination polymer using 2-(3’-hydroxy)phenyl benzimidazole as ligand and lanthanum as the central atom, was synthesized by hydrothermal synthesis method. We studied the effects of different reaction conditions on morphology of lanthanum coordination polymer.Moreover, EDS, FT-IR, TG-DTG, ICP and elemental analysis were employed to infer the possible structure and molecular formula of the complexes. Meanwhile, the interaction between it and ct-DNA under physiological conditions was studied by using a variety of methods, which including UV-vis absorbance spectroscopy,fluorescence spectroscopy, resonance light scattering spectroscopy(RLS), melting,viscosity and ionic strength method. UV-vis experiments shown that after adding various concentrations of ct-DNA, the complexes absorption bands occured significant hyperchromic effect, which suggested that the mode of interaction between the two was groove binding or electrostatic interaction. Further, according to melting point, viscosity, fluorescence polarization and ionic strength experimental results, it proved that the mode was groove binding not electrostatic interaction. According to Stern-Volmer and double logarithmic equation: it revealed that the quenching mechanism of La complexes by ct-DNA was mainly static quenching procedure;under three different temperatures(298,304,310K), the binding constants Ka were calculated 3.86, 2.79, and 1.48×103 L/mol respectively. The thermodynamic parameters ΔH(-98.39 KJ·mol-1), ΔS(-240.50 J·mol-1·K-1) and ΔG(-25.91 KJ·mol-1)were calculated by thermodynamic equation, and it could be inferred that the action forces were mainly van der Waals force and hydrogen bonds. RLS spectrum suggested that the complexes interact with base pairs of ct-DNA by way of hydrogen bonds, aggregating into large particles scatterer and resulting in RLS intensity increase.