Synthesis And Bioactivities Of Metal Complexes Of Quanternized Carboxylate Having Varied Fusion Ring Size

In the past decades, carboxylic metal complexes have been attracting considerable interest in the development of metal complexes as drugs due to that they contain a bioactive group of carboxylate which has strong coordination ability and diverse coordination mode. Therefore, to date, a large number of metal complexes of carboxylates have been synthesized and some of them have exhibited promising biological activities. On the other hand, metal complexes which contain conjugated acromatic ring or with positively charged functional groups, such as quaternary ammonium, may have strong DNA binding abilities. In this thesis, we designed three new kinds of quaterized carboxylate ligands having varied fusion ring size, which is pyridine, isoquinoline and phenanthroline, and synthesized their23metal complexes, which are summarized below.Part1:Reactions of quarterized carboxylic ligand HCbpBr (Cbp=N-(4-carboxybenzyl)pyridinium) with different tansitional metal salts in the presence of NaOH afforded eleven metal complexes of [Cu(Cbp)2(H2O)2](NO3)2·4H2O (1), [Cu2(Cbp)4Br2]·Br·OH·4H2O (2),[Cu2(Cbp)4(H2O)2](ClO4)4(3),[Zn(Cbp)2Br2](4),[Co(Cbp)2(H2O)4]·2Cl·4H2O (5),[Co(Cbp)2(H2O)4]3·4Cl·2OH·6H2O (6),[Co(Cbp)2(H2O)4]·2Br·4H2O (7),[Co(Cbp)2(CH3COO)2(H2O)2]·4H2O (8),[Co3(Cbp)8C(μ-OH)2(H2O)2](ClO4)4(9),[Ni(Cbp)2(H2O)4]·2Br·2H2O (10) and [Mn(Cbp)2Cl2](11), which were characterized by IR, elemental analyses and single crystal X-ray crystallography. Among these metal complexes, complexes1,4-8,10and11are mononuclear structure, complexes2and3are dinuclear structure and complex9is a trinuclear structure. In each mononuclear complex, the central metal ion is strongly coordinated to two unidentate Cbp ligands, then further coordinated to two water molecules in complex1, or to two halogen ions in complexes4and11, or to four water molecules in complexes5,6,7and10, or to two unidentate acetate and two water molecules in complex8, hence forming flat square (1), slightly distorted tetrahedral (4and11) or octahedral (5,6,7,8and10) coordination geometry. In complexes2and3, the centrosymmetric binuclear coppers bridged by four Cbp ligands and each copper(Ⅱ) ion further coordinated to one terminal Br-in complex2or one water molecules in3. Complex9is a trinuclear structure in which every two Co(Ⅱ) ions are bridged by two carboxylates and one hydroxo-O atom and the two peripheric cobalt ions further coordinated to two unidentate Cbp ligands and one H2O molecules. Three cobalt ions all showed octahedral coordination geometry. Ethidium bromide (EB) displacement experiments indicated that complexes1-3exhibited high binding affinity toward calf-thymus DNA. Agarose gel electrophoresis (GE) experiments indicated that complexes2and3were capable of converting pBR322DNA into open circular (OC). Kinetic assay for complex3afforded the maximal catalytic rate constantKmax of (1.52±0.47) h-1and Michaelis constant KM of (5.25±2.20) mM, respectively. The results imply that dinuclear copper metal complexes may show high DNA binding affinity and catalytic activity in DNA cleavage.Part2:Based on the results described in part one, we synthesized a new ligand of HCbiqBr (Cbiq=N-(4-carboxybenzyl)isoquinolinium) based on quaternized isoquinoline instead of quaternized pyridine, in order to enhance the bioactivities of metal complexes. Seven metal complexes:[Cu2(Cbiq)4(H2O)2]X, X=4C1(12),2Cl·2Br-4H2O (13),4Br·2H2O (14),(ClO4)4·4H2O (15),[Zn(Cbiq)2(H2O)2]Cbiq·2Br·H2O (16),[M3(Cbiq)8(μ-OH)2(H2O)2](ClO4)4·7H2O (M=Co (17), Mn (18)) were synthesized and characterized by IR and single-crystal X-ray crystallography. Complexes12-15have similar structure in which the centrosymmetric binuclear coppers are bridged by four Cbp ligands and each copper(Ⅱ) ion further coordinated to one water molecules. In complex16, the centre Zn ion is coordinated to two unidentate Cbp ligands and two H2O molecules, thereby forming a tetrahedral coordination geometry. Complexes17and18have similar structures in which every two M(Ⅱ) ions are bridged by two carboxylates and one hydroxo-O atom and the two peripheric metal ions further coordinated to two unidentate Cbp ligands and one H2O molecules. EB displacement and agarose GE experiments indicated that complexes12-15exhibited high DNA binding affinity and DNA cleaving activities. Kinetic assay of complex15afforded the maximal catalytic rate constant kmax of (2.80±0.97) h-1and Michaelis constant KM of (3.22±0.76) mM, respectively. The mechanistic pathway by complex15most probably involved the formation of singlet oxygen and hydrogen peroxide as the reactives pecies. The results also imply that dinuclear copper metal complexes may show high DNA binding affinity and catalytic activity in DNA cleavage.Part3:N-carbethoxymethyl-1,10-phenanthrolinium bromide (CempBr) and its five metal complexes,[Cemp]2[MCl4] where M=CuⅡ(19), ZnⅡ (20), CoⅡ (21), NiⅡ (22) and MnⅡ (23), were synthesized and characterized by1H NMR, ESI MS, elemental analyses, IR, UV-Vis, and single-crystal X-ray crystallography. Complexes19-23are structurally similar, and consist of isolated [Cemp]+cations and [MCl4]2-anions in which there are no obvious interactions between the oxygen or nitrogen donor atoms in [Cemp]+and the metal center in [MCl4]2-. Agarose GE studies on the cleavage of plasmid pBR322DNA by complexes19-23indicated that only complex19was capable of efficiently cleaving DNA under physiological conditions, most probably via an oxidative mechanism. Kinetic assay of complex19afforded the maximal catalytic rate constant kmax of (0.55±0.03) h"1and Michaelis constant KM of (47.6±6.6)μM, respectively, which gives about108-fold rate acceleration over uncatalyzed cleavage of supercoiled DNA. The high cleaving efficacy of complex19is thought to be due to the efficient catalysis of the copper(II)-coordinated center and the efficient binding of the quaternized1,10-phenanthroline cation to DNA. More significantly, the present results highlight the fact that, in addition to mono-, di-and multi-nuclear metal complexes, ionic metal complexes such as complex19may serve as effective catalysts for DNA cleavage as well.