Synthesis,Structural Characterization And Antitumor Activity Of The Novel Metal Complexes Of Anthracene Hydrazone Derivatives

Based on the chemical structure and its special anthracene hydrazone pharmacophore of bisantrene.as a clinically used anthracycline derivative antitumor drug,two novel anthracene hydrazone ligands and their nine complexes were synthesized and characterized in this dissertation.The structures of the compounds were fully characterized by IR,ESI-MS,NMR,elemental analysis and single crystal X-ray diffraction analysis.On the cellular level,the in vitro antitumor activities of the compounds were tested by MTT assay,towards several typical human tumor cell lines as well as the human normal liver cell line.On the molecular level,the interaction mechanisms of the compounds with DNA and Topoisomerase 1 was studied by agraose gel electrophoresis and fluorescence spectroscopy.These work provide important research data and experiences for exploring the better anthracene hydrazone derivatives and their antitumor metal complexes.Two anthracenehydrazone ligands are 9-AFPH and 9-AMPH.The nine complexes are 9-AFPH-Pt,9-AFPH-Rh,9-AFPH-Pd,9-AFPH-Cu,9-AFPH-Ni,9-AMPH-Pt,9-AMPH-Co,9-AMPH-Ni.All the above compounds were characterized by IR,ESI-MS,NMR,elemental analysis and single crystal X-ray diffraction analysis.On the cellular level,the anti-proliferative effect of all the compounds have been tested by MTT assay,and the IC50 values were calculated by Bliss method.Measured tumor cell lines include Ilep-G2,SK-OV-3,HeLa,T-24,NCI-H460,NCI-H460,with the above tumor cells and the human normal liver cell line HL-7702 were compared.The results showed that the inhibitory rate of the complexes 9-AFPH-Cu and 9-AFPH-Rh were significantly higher than that of the ligand 9-AFPH,and the inhibition rate was more than 50%at the concentration of 20 μmol/L,indicating their wide-spectrum tumor growth inhibition properties.The IC50 values of the complex 9-AFPH-Cu on multiple tumor cells were less than 20.The in vitro antitumor activity of the ligand 9-AMPH and its Pt,Co,Ni complex were not satisfying.The result suggested that the anthracene hydrazone side line and the metal centre are both important for the higher antitumor activity.So more related compounds need to be synthesized and characterized to better explain and understand the structure-activity relationship of this kind of metal complexes of novel anthracene hydrazone derivatives.On the molecular level,the antitumor mechanisms of the compounds with Topo I and DNA was studied by fluorescence spectroscopy and agraose gel electrophoresis.It is shown that the compounds are primarily bound to DNA by insertion.This result is consistent with the molecule mechanism of action of the classical anthracycline antitumor drugs.The higher antitumor activity of part of the metal complexes of 9-AFPH or 9-AMPH may be ascribed to the positively charged metal center,and a more ideal rigid plane of the complexes of anthracene hydrazone.In all,the research prospective of novel metal complexes of anthracene hydrazone is attractive to explore and discuss on the structure-activity relationship.More work need to be expanded and explored for better understanding and for developing better antitumor metal complexes of anthracene hydrazone.On the whole,The effect of ligand 9-AFPH and its metal complexes on the cellular and molecular levels is superior to that of ligand 9-AMPH and its metal complexes.The reason is presumed to be related to the side chain structure of the complex.The side chain of ligand 9-AFPH and its metal complex is 2-hydrazino-4-trifluoromethylpyrimidine,which has a certain electron-withdrawing effect.The side chain of the ligand 9-AMPH and its metal complex is 2-hydrazino-4,6-dimethylpyrimidine,which has a certain electron donor effect.