Studies On The Synthesis, Characterization And Bioactivities Of Novel Metal Complexes

Metal complexes are widely used in catalysis, medicine, analytical chemistry, corrosion and photochromic areas, etc. It is very important research focus in the field of bioinorganic. Cisplatin is a first metal complex-based anti-tumor drug, which is obtained by interaction with DNA and damaged the structure and function of DNA, leading to the failure in the process of tumor cell proliferation. In recent years, the ubiquitin-proteasome pathway (UPS) has become important issues of the anti-tumor activity, and the proteasome has become an important target for drug development. The proteasome inhibitors have become an important class of antitumor drugs. Daniel reported the synthesis of Cu[8-OHQ]2 which has a strong proteasome inhibitory activity and can induce apoptosis of tumor cells. Dr. Dou who is professor of Wayne State University research team reported a variety of metal complexes which can be used as a proteasome inhibitor, selectively induce MDA-MB-231 human breast cancer cells, PC3 human prostate cancer cells and MCF7 human breast cancer cells, etc. Metal complexes as antitumor drugs has become a hotspot of the coordination chemistry.In this paper, nineteen Schiff base metal complexes and five ternary metal complexes have been synthesized. The single crystals of three metal complexes have been obtained by natural evaporation method. The metal complexes have been characterized by single-crystal diffraction infrared spectroscopy, elemental analysis, UV spectroscopy, thermal gravimetric analysis,1H NMR analysis and molar conductivity analysis. Theoretical calculations of the three metal complexes have been studied. The fluorescence properties of metal complexes and the interaction between complexes and DNA have been tested, too. Moreover, the anti-tumor activity of all the metal complexes has been studied, and the mechanisms of the metal complexes inducing cancer cells apoptosis through inhibiting proteasome activity have been discussed. Finally, we studied that the DSF+Cd inhibit proliferation of human prostate cancer cells, and explored the mechanism of the action. The main research work of this paper are as the following aspects:(1) The Schiff base metal complexes derived from L-ornithine and 2,4-hydroxybenzaldehyde were synthesized. The composition of metal complexes are: [M(L1)2]·2H2O (M= Cu(Ⅱ), Pb(Ⅱ), Ni(Ⅱ), Zn(Ⅱ), Co(Ⅱ), Cd(Ⅱ) n= 0,1,2). Screened out that metal complex [Cd(L1)2]·2H2O can inhibit the proliferation of human prostate cancer LNCaP, human prostate cancer C4-2B and human breast cancer cell MDA-MB-231 by MTT assay. By western blot analysis, CT-like activity experiments and cellular morphological changes experiments, the mechanism of apoptosis induction were studied. Finally, proved that metal complex [Cd(L1)2]·2H2O as a proteasome inhibitor induced apoptosis in human cancer cells LNCaP, C4-2B and MDA-MB-231. The antitumor activity of [Cd(L1)2]·2H2O has a certain breadth.(2) The Schiff base metal complexes derived from L-ornithine and 2-hydroxy-naphthaldehyde were synthesized. The composition of metal complexes are:[M(L2)2]·2H2O (M = Cu(II), Pb(II), Ni(II), Zn(II), Co(II), Cd(II) n= 2,3). Screened out that metal complexes of [Cd(L2)2]·2H2O, [Cu(L2)2]·2H2O, [Zn(L2)2]·3H2O and [Ni(L2)2]·3H2O can inhibit the proliferation of human prostate cancer LNCaP, human prostate cancer C4-2B and human breast cancer cell MDA-MB-231 by MTT assay. The mechanism of [Cd(L2)2]·2H2O and [Cu(L2)2]·2H2O were studied. Finally, proved that metal complexes of [Cd(L2)2]·2H2O and [Cu(L2)2]·2H2O as proteasome inhibitors induce apoptosis in human cancer cells LNCaP, C4-2B and MDA-MB-231. The antitumor activities of [Cd(L2)2]·2H2O and [Cu(L2)2]·2H2O have a certain breadth too.(3) The Schiff base metal complexes derived from 2,2,6,6-tetramethyl-4-piperidone and 3-aminopyrazine-2-carboxylic acid were synthesized. The composition of metal complexes are: M(L3)2 (M= Cu(Ⅱ), Pb(Ⅱ), Ni(Ⅱ), Zn(Ⅱ), Co(Ⅱ), Cd(Ⅱ), Mn(Ⅱ)). The metal complex of Cd(L3)2 can inhibit the proliferation of human prostate cancer LNCaP. The mechanism of [Cd(L3)2] was studied. The metal complex of [Cd(L3)2] as proteasome inhibitors induced apoptosis in human cancer cells LNCaP. The Schiff base ligand L3 and metal complexe [Zn(L3)2] have solid fluorescence activity, while other complexes did not exhibit solid fluorescent activity, indicating that Cu(Ⅱ), Pb(Ⅱ), Ni(Ⅱ), Co(Ⅱ), Cd(Ⅱ), Mn(Ⅱ) have certain quenching effect on the fluorescent activity of Schiff base ligand L3.(4) Five ternary metal complexes derived from o-aminobenzonic and 1,10-phenanthroline were synthesized. The composition of metal complexes are: M(phen)(o-AB)2 (M= Cu(Ⅱ), Pb(Ⅱ), Ni(Ⅱ), Zn(Ⅱ), Cd(Ⅱ)). Obtained three crystals of [Zn(phen)(o-AB)2], [Cd(phen)(o-AB)2] and [Pb(phen)(o-AB)2]. Crystallographic data are as follows: ① The crystal crystallizes of [Zn(phen)(o-AB)2] in monoclinic, space group P2(1)/c with α= 7.6397(6) A, b= 16.8761(18) A, c= 17.7713(19) A, α= 90°,β= 98.9570(10)°, γ= 90°, V= 2.2633(4) nm3, Z= 4, F(000)= 1064, S= 1.058, Dc= 1.520 g·cm-3,R1= 0.0412, wR2= 0.0948,μ= 1.128 mm-1. ②The crystal crystallizes of [Cd(phen)(o-AB)2] in monoclinic, space group P2(1)/c with α= 7.6462(6) A,b= 17.1758(17) A, c= 17.7436(18) A, α= 90°,β= 100.1000(10)°, γ= 90°, V= 2.2941(4) nm3, Z= 4,F(000)= 1136,S= 1.035, Dc= 1.635 g·cm-3,R1= 0.0360, wR2= 0.0851,μ= 0.994 mm-1. ③ The crystal crystallizes of [Pb(phen)(o-AB)2] in triclinic, space group P-1 with α= 7.8127(6) A, b= 12.9880(11) A, c= 13.4150(12) A, α= 63.4960(10)°, β= 84.243(2)°, γ= 77.5180(10)°, V= 1.18937(17) nm3, Z= 2, F(000)= 636, S= 1.073, Dc=1.842 g·cm-3, R1= 0.0388, wR2= 0.0987, μ= 7.133 mm-1. All the three complexes are neutral compounds, which contains two o-aminobenzoic ligands and a 1,10-phenanthroline ligand. In complexes, metal ion is located in a octahedron coordination with six bonds to two N atoms from 1,10-phenanthroline and four carboxylate O atoms from two o-aminobenzoic acid molecules. There are two four-membered chelate rings and one five-membered chelate ring.Based on crystal datas, density functional theory (DFT) studies of the complex were performed using the Gaussian 03 program suite. Bond lengths, bond angles, frontier orbital distribution and natural charge distribution of complexes obtained from calculation determine the existence of stable crystal structure. The results indicate that some bond lengths and some angles data obtained from the calculations are agree with those gained from the determination. Explains that the calculation model is rational.The fluorescence properties of [Zn(phen)(o-AB)2], [Cd(phen)(o-AB)2] and [Pb(phen)(o-AB)2] have been measured. Their fluorescence emission spectra were compared with o-aminobenzonic and 1,10-phenanthroline. The interaction between complex [Cd(phen)(o-AB)2] and DNA have been tested by UV spectroscopy, fluorescence emission spectroscopy and viscosity measurement. The studies suggessting that the [Cd(phen)(o-AB)2] interact with DNA via electrostatic interration mode. Screened out that metal complex [Cd(phen)(o-AB)2] can inhibit the proliferation of human prostate cancer LNCaP, human prostate cancer C4-2B and human breast cancer cell of MDA-MB-231 by MTT assay.(5) The mixture of Cadmium and disulfiram can inhibit the proliferation of human prostate cancer LNCaP and human prostate cancer C4-2B. The androgen receptor AR is expressed in LNCaP and C4-2B cells, AR is very importat protein in the regulation of cell function and maintain cell growth. It was found that DSF+Cd can effectively inhibit the expression of AR in prostate tumor cells, which induces apoptosis in LNCaP and C4-2B cells. This discovery has a certain significance on treatment of prostate cancer.