Design, Synthesis And DNA-Cleaving Activities Of Metal Complexes Of Zwitterionic Carboxylates

In the past decades, metal complexes have been receiving much attention because of their diverse structural chemistry and potential applications in electronics, optics, sensing devices, magnetism, catalysis, gas adsorption and storage, luminescence, chiral separation and metal nucleases.Among those studies, metal complexes of carboxylates has been recieved much attention due to their applications in DNA cleavage. This is mainly because that carboxylates have strong coordination ability and diverse coordination modes, forming a large number of metal complexes with novel structures. That provides a good screening platform for effective DNA-cleaving agents. In this thesis, we synthesized two new types of water-soluble zwitterionic carboxylates, and their conrresponding 14 metal complexes. We also investgated the DNA binding and cleaving activities of these metal complexes. The obtained results are summarized below.Part 1:Reactions of zwitterionic dicarboxylic ligand H2CcbpBr (Ccbp= 4-carboxy-1-(4-carboxybenzyl)pyridinium) with different tansitional metal salts in the presence of NaOH afforded five metal complexes:{[Cu(Ccbp)2]·4H2O}n (1), [Ni(H2O)6](Ccbp)2·4H2O (2)?[M(Ccbp)2(H20)4]·2H2O·2MeOH (M= Zn (3), Co (4), Mn (5)). They were characterized by IR, elemental analyses and single crystal X-ray crystallography. Among them, complex 1 has a polyunclear structure, complex 2 is ionic complex, and complexes 3,4 and 5 have monounclear structures. In complex 1, the central metal ion is strongly coordinated to four unidentate Ccbp ligands to form a one-dimensional structure. Complex 2 consists of isolated [M(H2O)6]2+dications and [Ccbp] anions, between which there is no coordination. Complexes 3-5 have similar structures. The central metal ion is strongly coordinated to two Ccbp ligands, and then further coordinated to four water molecules, hence forming slightly distorted octahedral coordination geometry. Agarose gel electrophoresis studies on the cleavage of plasmid pBR322 DNA by complexes 1-5 indicate that only complex 1 was capable of efficiently cleaving DNA, most probably via an oxidative mechanism. Kinetic assay of complex 1 afforded the maximal catalytic rate constant kmax of 0.50 h-1, Michaelis constant KM of 0.60 mM and catalytic efficiency kmax/KM of 0.84 h-1mM-1, respectively. The high cleaving efficacy of complex 1 is thought to be due to its polynuclear structure.Part 2:Based on the results described in part one, four rare earth complexes [M(Ccbp)3(H2O)3]n(M=La? (6), Ce? (7), Pr? (8), and Nd? (9)) were synthesized from dicarboxylate ligand H2CcbpBr and characterized by elemental analyses, IR and single-crystal X-ray crystallography. Complexes 6-9 are isostructural in which every three Ccbp- ligands juxtapose two Ln3+ions in a monodentate coordination mode to form triple-stranded one-dimensional chain structures. Each central Ln3+ atom further associates with three H2O molecules, furnishing a monocapped square-antiprism geometry. Agarose gel electrophoresis studies indicate that 6-9 are capable of cleaving DNA in the presence of H2O2, most probably via an oxidative cleavage mechanism. Complexes 6 and 7 exhibited catalytic efficiencies (kmax/KM) of 37.69 h-1.mM-1 and 34.11 h-1·mM-1, respectively, are ca 15-and 20-fold more effective than complexes 8 (Kmax/KM= 1.75 h-1·mM-1) and 9 (kmax/KM= 2.21 h-1·mM-1), respectively. The results imply that rare earth complexes may show high DNA binding affinity and DNA-cleaving activity in the presence of H2O2.Part 3:Based on the previous two parts, we desiged a new tricarboxylic acid ligand, H3CmdcpBr (Cmdcp= N-carboxymethyl-(3,5-dicarboxyl)pyridinium) and synthesized its five copper complexes:{[Cu3(Cmdcp)2(OH)2(H2O)2]·H2O}n (10), {[Cu(Cmdcp)(H2O)2]·2H2O}n (11),{[Cu(Cmdcp)(2,2'-bipy)]·3H2O}n (12), {[Cu(Cmdcp)(H2O)2]·H2O}n (13) and{[Cu(Cmdcp)(phen)(H2O)]2-9H2O}n (14). All these copper complexes were characterized by IR, elemental analyses and single crystal X-ray crystallography. Among those complexes, complexes 10,13 and 14 possess one-dimensional polynuclear structures, whereas complexes 11 and 12 show two-dimensional network structures. Ethidium bromide (EB) displacement experiments indicated that complexes 12 and 14 exhibited high binding affinity toward calf-thymus DNA. Agarose gel electrophoresis (GE) experiments indicated that complexes 11,12 and 14 were capable of converting pBR322 DNA into open circular (OC). The (kmax's), (KM's) and catalytic efficiency kmax/KM obtained from the saturation kinetic profiles of the supercoiled DNA cleavage were (0.28 ±0.01) h-1, (371.8 ± 51.0)?M and 5.05 h-1 mM-1 for 11, (0.52 ± 0.08) h-1, (103.67 ± 24.23) ?M and 5.05 h-1 mM-1 for 12, (0.74 ± 0.09) h-1, (50.01 ± 13.11)?M and 14.8 h-1 mM-1 for 14, respectively. Complexes 11,12 and 14 functioned most probably via an oxidative cleavage mechanism. The results imply that a copper metal complex which treated with ligands of 2,2'-bipyridine and phenanthroline shows high DNA binding affinity and catalytic activity in DNA cleavage.