Studies On The DNA-binding Properties Of Rare Earth And Transition Metal Complexes Containing Drugs

The development of the interaction between small molecule and nucleic acid was fully described in the dissertation paper. It involves interaction modes and influence factors, research methods and research techniques. The development direction and development prospects were also expatiated.DNA is a main carrier of life information, is one of the logically potential target for drugs in pharmacology. Quinolones, biguanide, and sulfonylurea have extensive bioactivity. In order to explore the mechanism of them and their metal complexes in pharmacological activity including antibacterial, anticancer, and anti-diabetes activity, we investigated the interaction of DNA, nucleotide and four drugs and their rare earth complexes, three new salicylaldehyde derivative Schiff base and their Zn(II) complexes. Many methods were performed: UV-Vis absorption and fluorescence measurements, resonance light-scattering, circular dichroism, viscosity, and IR spectrum.Firstly, we prepared four novel rare earth complexes of HGA, the composition of complexes were investigated to be [RE(HGA)₃(H₂O)₂]Cl₃ (RE³⁺ = La³⁺, Nd³⁺, Eu³⁺, and Tb³⁺, the abbreviations of four complexes are LaL₃, NdL₃, EuL₃, and TbL₃), through elemental analysis, IR, molar conductivity, thermogravimetry/differential thermal analysis (TG-DTA), and fluorescence spectra. The binding behaviors of complexes and HGA to DNA and nucleotide are presented and discussed using UV-Vis absorption and fluorescence spectroscopy, and viscosity.The results suggest that both complexes and HGA bind to DNA via groove interaction, which is associated with the characteristic of complex structure: the piperazynyl moiety in Hgand of present complexes can not coplanar with the quinoline nucleus. And electrostatic force is another binding mode between complexes and DNA. The quenching mechanism of HGA and LaL₃ by DNA is ascribed to the electron transfer from guanine to the compounds; this transfer process did not happen between other complexes and DNA because the different characterizations of 4f electron shell of RE³⁺ ions. In addition, the binding strength of complexes to DNA is stronger than that of HGA; it can be assembled in following order: LaL₃ < NdL₃< EuL₃ < TbL₃, indicating that the species of central ion can effect on the binding affinities of complexes to DNA, while the force is not stronger. This result also supports the reasoning that these complexes may have stronger antibacterial activity than ligand.Secondly, the DNA-binding of neodymium complex with salicylacyl dimethylbiguanide (Nd(SG)3) were investigated. It was found that Nd(SG)3 interacts to DNA through non-classic intercalation mode, the intercalative part is the salicylacyl of ligand. The form of hydrogen bonding between the -OH group of salicylacyl and the nitrogen atom of guanidine makes the intercalative part possesses a greater planar area, hence it together with the synergistic enhancement between ligand and rare earth ions play the important role in the result: Nd(SG)3 is engaged in DNA binding intimately, which is consistent with the result that Nd(SG)3 has good anti-diabetes. This stronger DNA binding strength foreshows that Nd(SG)3 may has potential antibacterial or anticancer activity.Thirdly, we explored the DNA binding behaviors of four Nd(III), Eu(III) complexes containing tolbutamide (D₈₆₀, D) or chlorpropamide (CP): NdD, EuD, NdCP, and EuCP. It has been proved that they also interact to DNA through non-classic intercalation mode, but they exhibit stronger DNA binding affinity than Nd(SG)3. RLS spectra show that there are obvious long range assembly of these complexes on the molecular surface of DNA, indicates electrostatic force is another binding mode between them and DNA. This result also can get from the fact: the hypochromism of present complexes decrease with the increasing concentration of NaCl in buffer. The K_b values of NdD and EuD are higher than that of D₈₆₀ itself, which is ascribed to the synergistic enhancement of the ligand and rare earth ions. In addition, the coordination with metal ions decrease the possibility of forming hydrogen bonding with DNA, and decrease their resistance of intercalating to DNA, hence enhance their affinity with DNA. Present observations lead us to suspect that complexes have stronger bioactivity than ligand. In both UV-Vis absorption and viscosity measurements, four complexes exhibit same DNA-binding strength order: NdD > EuD, NdCP > EuCP. For these complexes with D₈₆₀ or CP, the influence force order of Nd³⁺ and Eu³⁺ is same: Nd³⁺ > Eu³⁺, which is contrary to complexes with gatifloxacin: Eu³⁺ > Nd³⁺. So it becomes evident that for different drug complexes, the influence force of Nd³⁺ and Eu³⁺ in DNA-binding is different.Fourth, three new Schiff base ligandsN-(3-formyl-5-methylsalicylidene)-2-aminoethanol (H₂L¹),N-(3-hydroxylmethyl-5-methylsalicylidene)-2-aminoethanol (H₃L²),2,6-bis(o-carboxyphenyliminomethene)-4-methylphenol (H₃L³) and their binuclear Zn( II) complexes [Zn₂(HL¹)₂]Cl₂-2H₂O (ZnHL¹), [Zn₂(H₂L²)₂]Cl₂·H₂O (ZnH₂L²) and [Zn₂(HL³)Cl₂]·H₂O (ZnHL³) were synthesized and characterized by ¹H NMR, elemental analysis, IR and molar conductivity. The DNA-binding of these complexes were investigated. Mechanistic studies show that ZnHL¹ and ZnHL³ can bind to DNA by intercalative mode, and the latter intercalates into DNA more efficiently than the former, while ZnH₂L² binds to DNA by hydrogen bonding interaction on the grooves of DNA host. All of these results further support the fact that modification of the ligands can produce interesting differences in the space configuration, which lead to some differences in spectral properties, DNA binding mode and strength of complexes.The scavenging ability of ligands can be assembled in following order: H₃L²>H₂L¹>H₃L³. It can be first elucidated by the mechanism that the electron-releasing group (-CH2OH) can stabilize the phenoxyl radical, in contrast, electron-attracting groups (-CHO,-C=N-Ph) induces inverse result. Second, the phenoxyl radical derived from H₃L² can be further stabilized by forming intramolecular hydrogen bonding between itself and o-position group. Moreover, the scavenging ability accords with the amount of hydroxyl in ligands. After coordination with Zn²⁺, the phenolic hydroxyl can more easily give off H⁺, and H⁺ will form a stable compound with·OH. So the scavenging ability of complexes is stronger than their corresponding ligands. This experimental and theoretical information will be useful in design of new drugs and therapeutic reagents.