Polynuclear Metal Complexes: Design, Synthesis And DNA Binding Properties

Cancer and tumor have become a threat to human health. Drugs targeting DNA caninhibit cancer cell growth and proliferation fundamentally, which are the most promisinganti-cancer and anti-tumor drugs. Due to characteristics such as multiple metal centers,multi-targets, better binding properties of DNA and others, polynuclear metal complexes canprovide new design ideas for the development of novel anti-tumor and anti-cancer drugs. Theaim of this study is seeking polynuclear metal complexes with novel structure type that canspecifically recognize DNA secondary structure. The main works of this thesis are dividedinto two parts as following:In part one, the tetradentate schiff base ligands based on triphenylamine and pyridine(L1-L3), chelated two nickel metals to synthesize three cylindrical binuclear complexes[Ni2(L1)3][ClO4]4,[Ni2(L2)3][ClO4]4,[Ni2(L3)3][ClO4]4, which are similar to the structure ofzinc finger proteins. Through UV, circular dichroism and FRET-melting experiment to studythe binding mode and binding ability of the cylindrical dinuclear metal complexes withG4-DNA, and to explore their interaction mechanism with G4-DNA. The results showed thatthey had a higher binding with G4-DNA constant (Kb=0.11-2.2×106M1), and were thepreferred DNA binders. The cylindrical polynuclear metal complexes stacked on the top ofG4-DNA, could significantly improve the stabilization of G4-DNA (Tmup to24.5°C) andhad a modest degree of selectivity for the quadruplex DNA versus duplex DNA(>10fold).CD experiments exhibited that Ni2(L1)34+could promote antiparallel G4-DNA to form hybridG4-DNA structure in the Na+buffer solution and had the strongest effect on G4-DNA in thethree complexes.In part two, six tetrahedral polynuclear metal complexes with eight positive charges weredesigned and synthesized, their binding abilities and modes on ct-DNA or G4-DNA and theabilities to selective recognize on G4-DNA have been studied systematically. Details dividedinto three areas:1) The biphenyl diamines interacted with the pyridine/imidazoleformaldehyde by condensation reaction, then chelated metal (FeII/NiII), to synthesis sixtetrahedral polynuclear metal complexes [M4(L)6]8+(M=FeII/NiII, L=L4-L7). The series oftetrahedral polynuclear metal complexes were characterized by elemental analysis, IRspectroscopy, UV spectroscopy, nuclear magnetic resonance spectroscopy and massspectrometry.2) Studying the interactions of tetrahedral polynuclear metal complexes andct-DNA though the meathods of UV titration spectroscopy, circular dichroism, fluorescencespectroscopy and gel electrophoresis assay. The results showed that tetrahedral polynuclear metal complexes interacted strongly with ct-DNA in the major groove in electrostaticinteraction, exhibited good binding properties (binding constant Kb=1.4-3.8×105M1, theapparent binding constant Kapp=5.0-10.2×106M1), and induced the bending of ct-DNA insome extent.3) Studying the interactions of tetrahedral polynuclear metal complexes andG4-DNA though UV, circular dichroism, FRET-melting and competition experiment, whichshowed that they could stack on the end of G4-DNA and had the strong binding properties(binding constant Kb=1.1-4.2×106M1) and a modest degree of selectivity for thequadruplex DNA.[Fe4(L4)6]8+and [Fe4(L5)6]8+could stabilize the antiparallel (Tm=23.0°C,17.6°C) and hybrid (Tm=21.1°C,18.6°C) structure of G4-DNA. Four kinds of nickelcomplexes changed the secondary structure of G4-DNA with higher ΔTmvalue.