Synthesis,Crystal Structure And Antitumor Activity Of The Metal Complexes Bearing Novel Anthracene Hydrazone Derivatives

Based on the structure and its special anthracene hydrazone pharmacophore of bisantrene,which is a successful anthracycline antitumor drug,three novel anthracene hydrazone ligands and their six novel complexes were synthesized in this dissertation.All the compounds were detailed characterized by IR,EA,ESI-MS,NMR and single X-ray crystal diffraction analysis.Their antitumor activities in vitro were tested by MTT assay.The interaction mechanisms of the synthesized compounds with DNA and Topoisomerase was studied by fluorescence and CD spectroscopy,as well as agraose gel electrophoresis.This work provides an important fundamental basis and scientific data for the further antitumor activity research on such new metal complexes of anthracene hydrazone.Three synthesized anthracene hydrazone ligands are(9-Anthracenecarboxaldehyde,2-(2-pyridinyl)hydrazone,9-APH),(9.10-Anthracenedicarboxaldehyde.9-[2-(2-pyridinyl)hydrazone].9.10-AAPH).(9.10-Anthracenedicarboxaldehyde.9-[2-(4.5-dihydro-1H-imidazol-2-yl)hydrazone],9,10-AAIH).The six complexes are 9-APH-Pt(Ⅱ),9-APH-Cu(Ⅱ).9-APH-Co(Ⅱ),9-APH-Ni(Ⅱ),9,10-AAPH-Pt(Ⅱ)and 9,0-AAIH-Pt(Ⅱ),respectively.All the compounds were detailed characterized by IR.EA,ESI-MS,NMR and single X-ray crystal diffraction analysis.The anti-proliferative effect of all the synthesized compounds were tested by MTT assay,and their IC50 values were calculated through Bliss method,based on the inhibitory ratios under the gradual concentrations.Seven human tumor cell lines(NCI-H460,Hep-G2,Bel-7404,SK-OV-3,MGC80-3,HeLa,T-24)and one human normal liver cell line HL-7702 were chosen for screening in this MTT assay.The experiment results show that:(1).9,10-AAIH showed the highest cytotoxicity against the selected tumor cell lines among the three synthesized ligands.(2).9-APH-Cu(Ⅱ),9-APH-Pt(Ⅱ),9,10-AAIH-Pt(Ⅱ)showed higher cytotoxicities against the selected tumor cell lines among the six synthesized complexes,suggesting that they are typical cytotoxic antitumor agents.(3).According to the principle of low toxicity and cytotoxic selectivity in the chemical drugs screening,9-APH-Pt(Ⅱ)and 9,10-AAPH-Pt(Ⅱ)show superior low toxicity and cytotoxic selectivity comparing the normal cell line HL-7702 with the tumor cell line T-24.Their IC50 values against T-24 were 14.12±1.78 μM and 17.07±1.19 μM,respectively,but were both higher than 100 μM against HL-7702.On the molecular level,the antitumor mechanisms of the synthesized compounds with DNA and Topo I was studied through fluorescence spectroscopy,CD spectroscopy and agraose gel electrophoresis.The results indicated that the synthesized compounds mainly interacted with DNA by intercalative binding mode via the planar anthracene structure.The metal complexes showed stronger intercalative binding with DNA than the corresponding ligands.This might be partly owing to the electro static attraction with DNA of the central positive metal cation,and a better rigid planarity of the metal complexes.In all,in this dissertation,a series of metal complexes of the novel anthracene hydrazone ligands were studied on their structures,antitumor activities and action mechanism.The research results provided important scientific data and fundamental basis for further developing the metal complexes of anthracene hydrazone ligands as new promising antitumor agents.