Synthesis, Characterization Of The Metal Complexes Involving Polyamide Compounds And Their Interaction With DNA

In this thesis, several novel symmetrical polyamides and their metal complexes had been synthesized, their structures had been characterized by ¹H NMR, ¹³C NMR, IR spectrum, MS, melting point determination, elements analysis and density functional theory (DFT) calculations. The interactions between these metal complexes and calf thymus DNA had been investigated by using UV, fluorescence, viscosity, DNA thermal denaturation, and CV (cyclic voltammetry). The cleavage reaction on plasmid DNA had been monitored by agarose gel electrophoresis. My major works are as follow: First, a novel symmetrical polyamides containing pyrroles, N¹,N⁸-bis (1-methyl-4-nitropyrrole-2-carbonyl)triethylenetetramine, and its copper(â…¡) complex had been synthesized. The complex can bind with DNA by classical intercalation and cleave DNA effectively. The effects of copper(â…¡) complex on cell viability were tested using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) dye assay and the results indicated that the complex had certain effect on cancer cells. The metal complex was a new chemical nuclease that has anticancer activity confirmed at both molecular and cellular levels.Second, a new symmetrical polyamides containing pyrroles, N¹, N⁸-bis (1-methyl-4-nitropyrrole-2-carbonyl)triethylenetetramine, and its magnesium (â…¡) complex had been synthesized. The experimental results show that the magnesium (â…¡) complex can bind to DNA by nonclassical electrostatic mode and cleave DNA effectively.Third, The complexes [Fe(Sal₂trien)]NO₃(Sal = salicylaldehyde, trien = triethylenetetramine) had been synthesized and its interaction with calf thymus DNA had been investigated. The results indicated that the Fe(â…¢) complex can bind with DNA by nonclassical electrostatic mode and cleave DNA effectively.Forth, a new metal complex Cu(Sal₂trien) had been synthesized and its interaction with calf thymus DNA had been investigated. A series of experimental results showed that the copper(â…¡) complex could bind to DNA by classical intercalation mode and cleave DNA effectively.Fifth, the metal complex Fe (Sal₂dienNO₃) (Sal = salicylaldehyde, dien = diethylenetriamine) had been synthesized and its interaction with calf thymus DNA had beentested. The experimental results indicated that the Fe(â…¢) complex can bind to DNA by classical intercalation mode and cleave DNA effectively.Sixth, two new symmetrical polyamides containing imidazole, N¹, N⁵-bis(1-methylimidazole-2-carbonyl)diethylenetriamine and N¹, N⁸-bis(1-methylimidazole-2-carbonyl)triethylenetetramine, had been synthesized and their structures had been characterized by ¹H NMR, ¹³C NMR, IR, MS, melting point deterlnination and elements analysis.Cancer is one of the most major diseases that endanger human life seriously. The death rate of cancer patients is up to 25% or so in the world now. In order to conquer the disease, scientists have been making great efforts to defeat it. With knowledge increasing about molecular biology of tumor, people have gotten outstanding achievements in therapy of cancer. Meanwhile many medicines have been applied to clinical treatment. Unfortunately, nearly all of the reagents have poor selectivity to tumor cells; they will damage normal cells while killing malignant tumor cells. Therefore, it is critical to improve the selectivity, increase efficiency and decrease side effect of anticancer medicines.The progresses of molecular biology and molecular pharmacology makes people understand some life phenomena at genetic level and search for the sensitive probes of nucleic acid as well as effective anticancer drugs. Most anticancer reagents act on DNA as their targets and the interactions include three kinds of modes: (1) An Anti-cancer drug binds with DNA as its template to form a non-covalent complex, mainly through hydrogen bonding. The reagent will separate from DNA when double helix of DNA is dissociated. (2) The reagent bind with DNA to form covalent complex, i.e. mainly through covalent bonds. If lying between double strands of DNA, it cross-links with the double strands and impede the disconnection of double strands of DNA. (3) The reagent combines with DNA selectively and makes the structure of the double strands unstable, leading to the single or double strands of DNA to break up. Thus it can degrade DNA template. It is easy to understand that it would be the Holy Grail for human race to find new chemical nucleases to cleave DNA at the predetermined site, such anticancer reagents would be able to destroy cancer cells while do the least harm to normal cells.Numerous control mechanisms in the living cell are based on the recognition and interaction between biological activity molecules and biomacromolecules. The design and synthesis of ligands that read the information form DNA duplex has been a central goal at the interface of chemistry and biology. Syntheses of DNA-binding molecules, such as triplex-forming oligonucleotides, peptide nucleic acids, oligosaccharides and oligopeptides, have been exploited extensively. Polyamides containing N-methylpyrrole and N-methylimidazole amino acids have attracted considerable attention on the part of synthetic and biological groove of predetermined DNA sequences with high affinity and specificity. Since these polyamides can permeate living cell membranes, they have the potential to control specific gene expression. The principal rules developed by Dervan et al. are that antiparallel pairing of Py/Im (Py = N-methylpyrrole and Im = N-methylimidazole) targets a C, G base pair, Im/Py targets a G, C base pair, and Py/Py is degenerate, recognizing either an A, T or T, A base pair. Furthermore, many useful complexes can be created by polyamides coordinating with other various molecules. Many studies showed that polyamides have great potential in curing congenital genetic and acquired immunity disease because they can transfer nucleic acid medicines safely, innocuously and high efficiently. Therefore, the study on the interactions of polyamides and their metal complexes with DNA is significant.We have focused our work on polyamides and their metal complexes, which can interact with DNA and cleave DNA effectively. The significance of our works is mainly as follows: First, the synthesized compounds, N¹, N⁸-bis (1-methyl-4-nitropyrrole-2-carbonyl)triethylenetetramine, H₂Sal₂dien, N¹,N⁵-bis(1-methylimidazole-2-carbonyl)diethylenetriamine, N¹, N⁸-bis(1-methyl-imidazole-2-carbonyl)triethylenetetramine, are all the new compounds; Second, all synthesized metal complexes had been confirmed to bind with DNA and to cleave DNA effectively. Therefore, all of them are new and effect chemical nucleases; Third, based on these compounds, a series of symmetrical polyamides and their metal complexes can be synthesized, which are anticipated to specifically cleave DNA at different predetermined site.To sum up, we had synthesized several novel symmetrical polyamides and their metal complexes with interesting DNA binding and cleaving properties. The aim is to discover a series of new chemical nucleases that can recognize and cleave DNA at predetermined site. The results should be valuable in understanding the mode of the complex with DNA as well as laying a foundation for the rational design of novel, powerful agents for probing and targeting nucleic acids. These should provide valuable information for exploring and developing new drugs and their application in the field of molecular biology. Thus, new chemical nucleases and anticancer medicines may be exploited and developed.