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

Bisantrene,as for clinically antitumor drugs,based on the unique chemical structure with its special anthracene hydrazone pharmacophore,three novel anthracene hydrazone ligands and fourteen transition complexes were synthesized and characterized in this dissertation.The structures of these compounds were characterized by ESI-MS,IR,elemental analysis and single crystal X-ray diffraction analysis.On the cellular level,the in vitro antitumor activities of these seventeen compounds were screened by MTT assay and their cell cycle,cell apoptosis induction were examined by flow cytometry and ICP-MS.On the molecular level,the interaction mechanisms bewteen compounds and DNA and Topoisomerase I were tested by fluorescence spectroscopy and agraose gel electrophoresis.The main contents are as follows:Three kinds of anthracene hydrazone ligands were synthesized,which were 9-PMAH,AMPMAH and APMAH.Their fourteen compounds were 9-PMAH-Pt（Ⅱ）,9-PMAH-Pd（Ⅱ）,9-PMAH-Rh（ⅡI）,9-PMAH-Cu（Ⅱ）,9-PMAH-Co（Ⅱ）,9-PMAH-Ni（Ⅱ）,AMPMAH-Pt（Ⅱ）,AMPMAH-Pd（Ⅱ）,AMPMAH-Rh（Ⅲ）,AMPMAH-Ir（Ⅲ）,AMPMAH-Cu（Ⅱ）,AMPMAH-Co（Ⅱ）,AMPMAH-Ni（Ⅱ）and APMAH-Pt（Ⅱ）,characterizing with IR,elemental analysis,ESI-MS,NMR and single crystal X-ray diffraction analysis.Finally tested the stability of all compounds in solution by UV spectrophotometer.On the cellular level,tested the anti-proliferative effect of all compounds though MTT assay and obtainied the IC₅₀ values by Bliss method.Comparing the tumor cell lines including T-24,Hep-G2,SK-OV-3,He La,NCI-H460,MGC80-3 to the human normal cell lines HL-7702,the results suggested that one of the ligands,9-PMAH,was higher than the others,and its complex9-PMAH-Pt（Ⅱ）has the same anti-proliferative effect.APMAH-Pt（Ⅱ）showed selectivity to Hela cell lines obviously.And the complex 9-PMAH-Cu（Ⅱ）expressed highest cytotoxicity towards these six tumor cell lines than the other complexes,with the IC₅₀ values lower than 5μM.Aiming to T-24 cell line,six of these complexes were examined for their cycle arrest and cell apoptosis induction via flow cytometry.The cell cycle experimental results implied all of them arrested the cell cycle in G2 phase.In the meantime,they could induce cell apoptosis totally.Afterwards,the distribution of drugs on T-24 cells were tested by ICP-MS,the experimental phenomena told us that copper complexes and iridium complex were mainly located in cell membrane fraction and nucleus fraction,respectively.The consequence reminded that numerous vital physiological processes via differently mechanisms.On the molecular lever,the antitumor mechanisms of the compounds with Topo Ⅰ and DNA was examined by fluorescence spectroscopy and agraose gel electrophoresis.The whole compounds were bound to DNA by insertion.The fluorescence quenching constant were stronger.And all compounds were strong Topo Ⅰ inhibitors.On the whole,from the perspective of structure-activity relationship,the ligand,9-PMAH and its complexes distinguished better anti-proliferative effect from the others.It was highly to explore the anticancer activity of anthracene hydrazone compounds by the method of constructing the structure-activity relationship.