Studies On Synthesis, Structure And Biological Activity Of Bridged Polynuciear Complexes And Polymers Based On DNA-binding

Studies on developing new inorganic drugs with high efficiency, low toxicity and specific target and their mechanism are of great interest in the field of inorganic pharmaceutical chemistry. Since the mechanism of inorganic drugs may be concerned with the coordination chemistry of metal ions, synthesis of metal complexes with pharmacological activity has provided a basis for the screening of inorganic drugs. Therefore, investigations on the design, synthesis and pharmacological activity of novel metal complexes have important academic value and potential appli-cation prospects for finding inorganic drugs of high efficiency and low toxicity.Based on the important physiological functions in living systems and the DNA-targeting effect of polynuclear complexes and coordination polymers, a series of polynuclear complexes and coordination polymers bridged by symmetric and asymmetric N,N’-bis(substituted)oxalamide were synthesized and characterized. The DNA interaction, anticancer activity and inhibition of helicobacter pylori of these compounds were investigated, and the anticancer mechanism was also preliminary studied. This thesis consists of four sections as follows:1. Synthesis and structure of polynuclear complexes and coordination polymers:in this paper, a series of bridged polynuclear complexes and coordination polymers are synthesized using symmetric and asymmetric N,N’-bis(substituted)-oxalamide as bridging ligands based on the synthesis techniques of coordination chemistry and the basic principles of assembling coordination polymers, and their structures have been characterized by single-crystal X-ray diffraction. By choosing N-(2-carboxyphenyl)-N’-[(2-amino)ethyl]oxamide (Hsbdeox) as bridging ligand, three compounds are synthesized, including one tricopper(II) complex [Cu3(bdeox)-(phen)3(H2O)](ClO4)3·H2O (1), and two one-dimensional coordination polymers {[Cu2(bdeox)(bpy)](ClO4)}n·nCH3OH (2) and{[Cu2(bdeox)(Me2bpy)](ClO4)}n (3). Using N,N’-bis(3-dimethylaminopropyl)oxalamide (H2dmapo) as bridging ligand, four one-dimensional polymers,Cu4(dmapo)2(SCN)4(CH3CH2OH)2]n·nCH3CH2OH (4), [Cu2(dmapo)(NO2)2]n (5), [Cu2(H2O)2(dmapo)(ipa)2]n·nCH3OH (6) and [Cu2(H2O)2-(dmapo)(tpa)2]n-nCH3OH (7) and two two-dimensional coordination polymers [Cu4(H2O)4(dmapo)2btc)]n-5nH2O (8) and [Cu2(dmapo)(pic)2]n-2nCH3OH (9) are synthesized. All the compounds are the first reported among similar compounds internationally, which provides a chemical foundation for the screening of non-platinum metal drugs.2. The non-covalent interaction of compounds with DNA:The rules of interactions of the compounds above and another four binuclear complexes [Cu2(dmapo)(phen)2](ClO4)2 (10), [Cu2(dmapo)(bpy)2](ClO4)2 (11), [Cu2(dmapo)-(Me2bpy)2](ClO4)2·4H2O (12), [Ni2(dmapo)(bpy)2(CH3OH)2](C104)2-2CH3OH (13) with Herring sperm DNA(HS-DNA) were studied by using spectral, electrochemical methods and viscometry. The results revealed that all these compounds can interact with HS-DNA via the non-covalent interaction. The study of bonding modes and bonding abilities between these compounds and the DNA provides theoretical basis for exploring the anticancer mechanism of DNA-targeting compounds on the molecular level.3. The antitumor activity and mechanisms of the compounds:The in vitro cytotoxicity studies of these compounds against two cancer cell lines, human gastric cancer cell line SGC-7901 and human hepatoma cell line HepG 2 were tested by MTT assay. The results indicate that all the compounds have certain cytotoxicities against SGC-7901 and HepG 2 cell lines. The IC50 values of (1), (2), (8), (10), (11) and (13) against the two cell lines are less than 20 μM, and (10) showed a certain selective inhibition of SGC-7901 cell lines. The results of flow cytometry showed that these compounds can arrest the cell cycle of HepG 2 cells at different degrees and phases to inhibit the proliferation of cancer cells. Compounds (1), (2), (4), (7), (10) and (13) can arrest the cell cycle of HepG 2 cells in G1/G0 phrase, (5), (6), (8), (11) and (12) can G1/G0 and G2/M phrase. The results of Hoechst staining showed that arrest the cell cycle in G2/M phrase, and (3), (9) can arrest the cell cycle in the two compounds inducing the cancer cell death by apoptosis. This part provides valuable information for exploring the anticancer activity and mechanism of these compounds at the cellular level.4. Inhibitory activity of Helicobacter pylori:Helicobacter pylori (Hp) is a class I carcinogenic factor for gastric cancer, and it may also lead to incidence and deterioration of liver cancer. It is found that (2) and (8) have obvious inhibiting effect on the growth of Hp by agar dilution method, and their minimal inhibitory concentration (MIC) are 25 μM and 12.5μM, respectively.This research above provides valuable information for the design and synthesis of non-platinum inorganic drugs.