Studies On The Synthesis,Structural Characterization And Antitumor Activity Of Metal Complexes Of 6-Methoxy-1-Pyridine-β-Carboline And 1-Pyrindine-β-Carboline Alkaloid

β-carboline alkaloids were originally isolated from the plant Peganum harmala,which showed broad spectrum pharmacological activities.Powdered seeds of Peganum harmala have been used in herbal formulas of traditional Chinese medicines to cure digestive tract tumors.Based on such background,in this dissertation,two β-carboline derivatives,6-methoxy1-pyridine-β-carboline(6-OMe-1-Py-βC)and 1-pyridine-β-carboline(1-Py-βC),were synthesized as the antitumoral ligands to give 19 metal complexes,containing 8 potential pharmacological activity metal ions,manganese,cobalt,nickel,copper,zinc,tin,platinum,gold.These complexes were achieved by solvothermal method or solution method.They were structurally characterized by IR,NMR,ESI-MS,and single-crystal X-ray diffraction analysis.On the cellular level,the antitumor activities of all the ligands and their metal complexes were assayed by MTT method.Then we performed flow cytometry to determine whether these compounds exhibited apoptosis-induction activity on the tested cell lines.On the molecular level,the interaction of all the ligands and their metal complexes with the potential target DNA were investigated by CD spectrometry and agarose gel electrophoresis assay.These studies afforded the research basis for the novel antitumor metal complexes bearing 6-methoxy-1-pyridine-β-carboline and 1-pyridine-β-carboline.The main contents of this dissertation as follows:1.We have synthesized 19 metal complexes with 6-OMe-1-Py-βC and 1-Py-βC by means of solvothermal or solution methods,respectively.They are as follows:[MnⅡ(6-OMe-l-Py-βC)Cl(μ2-Cl)]2(1)[SnⅣ(6-OMe-1-Py-βC)Cl4](6)[CoⅡ(6-OMe-1-Py-βC)Cl(μ2-Cl)]2(2)[PtⅡ(6-OMe-1-Py-βC)Cl2](7)[NiⅡ(6-OMe-l-Py-βC)Cl(μ2-Cl)]2(3)[AuⅢ(6-OMe-1-Py-βC)Cl2]·Cl(8)[CuⅡ(6-OMe-l-Py-βC)Cl2](4)[NiⅡ(6-OMe-1-Py-βC)2(N03)(CH30H)]·NO3{Znn[(6-OMe-l-Py-3C)-H]2}(5)(9)[CuⅡ(6-OMe-1-Py-βC)(N03)2(H20)](10)[CuⅡ(1-Py-βC)Cl2](15)[ZnⅡ(6-OMe-1-Py-βC)(N03)2](11)[CuⅡ(1-Py-PC)Cl2(DMSO)](16)[MnⅡ(1-Py-βC)Cl2(DMSO)](12){ZnⅡ[(1-Py-βC)-H]2}(17)[CoⅡ(1-Py-βC)Cl(μ2-Cl)]2(13)[SnⅣ(l-Py-βC)Cl4](18)[NiⅡ(1-Py-βC)Cl(μ2-Cl)(C2H5OH)]2(14)[PtⅡ(1-Py-βC)C12(19)All of the metal complexes have been fully structurally characterized by IR,NMR,ESI-MS,single-crystal X-ray diffraction analysis.The single-crystal X-ray diffraction analysis showed that complexes 1,2,3,13,14 were formed in binuclear structure,the others were formed in mononuclear structure.2.The in vitro antitumor activity of the two β-carboline derivatives and their metal complexes have been screened by MTT method at 20 μM concentration against six tumor cell lines,T-24,OS-RC-2,NCI-H-460,SK-OV-3,Hep-G2,MGC-803 as well as one human normal liver cell line HL-7702.The complexes 3,9,14 with better antitumor activity were chosen for the further research of cell cycle and apoptosis of tumor cell lines MGC-803 and OS-RC-2.The MTT results show that both the ligands and their metal complexes exhibit a certain growth inhibition ability to the different tumor cell lines.The nickel complexes of 3,9,14 show higher antitumor activities against to each tumor cell lines with approach or beyond 50%inhibition ratio under the concentration of 20 μM.The IC50 value of complexes 3,9,14 against to MGC-803 are 8.26±0.35,3.77±0.06,3.04±0.23,respectively.The IC50 value of complexes 3,9 against to OS-RC-2 are 11.11±1.67,11.35±0.06,respectively.The Flow Cytometer results show that complexes 3,9,14 can induce apoptosis of MGC-803.Meanwhile,complexes 3,9 can induce apoptosis of OS-RC-2.The cell cycle arrest test shows that complex 3 can retard the MGC-803 tumor cell in G1 phase,and complexes 9,14 arrest the MGC-803 tumor cell in S phase.However,complexes 3,9 show no retardant effect for cell cycle.Caspase-3 activation experiment shows that complexes 3,9,14 can induce apoptosis through activating caspase-3.3.The interaction of all the ligands and their metal complexes with potential target DNA were investigated by CD spectrometry and agarose gel electrophoresis assay.The CD results showed that the ligands 6-OMe-1-Py-βC,1-Py-βC and the complexes 2,3,4,5,8,9,10,11,12,13,14,17,19 might bind with ct-DNA in an intercalative mode,while the other compounds did not show significant DNA binding ability.In the agarose gel electrophoresis assay,complexes 8,19 showed ability on unwinding the supercoiled plasmid DNA and decreasing the electrophoretic mobility of DNA.