Synthesis And Anticancer Activity Of Acylhydrazone Copper(Ⅱ) Complexes Derived From Water-soluble Porphyrin

In this thesis,we have designed and synthesised nine acylhydrazone Cu（Ⅱ）complexes derived from water-soluble porphyrin,the ¹HNMR,MS,FT-IR and Elemental Anal were used to characterize their structures.Various physicochemical approaches were employed to study the interaction of the complexes and ct-DNA;The in vitro anticancer activity of the complexes were also tested,which will provide a certain basis for the study of water-soluble porphyrin acylhydrazone complexes in the fields of medicine and biology.The mainly research contents are as follows:1.we have introduced the present situation of cancer,the significance of research and synthesis status of water-soluble porphyrins compounds,the interaction between metalloporphyrins and DNA and the research progress of its anticancer activity in vitro.2.Three substituted benzoylhydrazone Cu（Ⅱ）complexes（named as Cu P1～Cu P3）derived from water-soluble porphyrin have been prepared and isolated successfully.The binding affinity of them with ct-DNA were tested by absorption titrations,Et Br quenching assays,ICD studies,viscosity and cyclic voltammetry measurement,the results showed that Cu P3 bound to ct-DNA stronger than Cu P1 and Cu P2 due to the nitro group in its acylhydrazone part.The cytotoxicity of complexes and ligands in human cancer cell line（A549 and H-1975 lung cancer cells,Hep G2 human hepatocarcinoma,T47D breast cancer cells）and noncancerous cell line（Hs 578Bst normal breast cells）have also been evaluated by MTT assay,the results demonstrated that all complexes have good cytotoxicity to cancer cells but weak cytotoxicity to normal cells.It is noteworthy that the ligands exhibited less cytotoxicity than complexes,which confirmed that the tumor selectivity of porphyrin compounds and the crucial role of Cu²⁺in improving the anticancer activity.Cell absorption experiment and fluorescence imaging experimental results indicated that Cu P1 and Cu P3 could induce the H-1975 cells or Hep G2 cell apoptosis,and Cu P1 induced H-1975 cells apoptosis mainly by accumulated cells in the G2 phase,while Cu P3accumulated Hep G2 cells in the S phase.3.Three fluorinated benzoylhydrazone Cu（Ⅱ）complexes（Cu P4～Cu P6）derived from water-soluble porphyrin have been designed and synthesis.Diversiform physicochemical approaches demonstrated that all of the complexes possess excellent binding affinity with ct-DNA,especially Cu P6 exhibited strongest binding affinity than its analogues,it could be ascribed that Cu P6 contains more fluorine atoms in hydrazone moiety,which can improve its amphiphilic property.MTT assay indicated that complexes Cu P4～Cu P6 have good cytotoxicity to cancer cells（A549,H-1975,Hep G2,T47D）but weak cytotoxicity to normal cells（Hs 578Bst）,In addition,the cytotoxicity of the ligands was far less than that of the complexes,which fully demonstrated that the coordination of the ligands with copper ions significantly improved the cytotoxicity.The flow cytometric analysis results illustrated that the complex Cu P6 mainly caused an accumulation of H-1975 cells in the G2 phase.4.Three keto acylhydrazone Cu（Ⅱ）complexes（Cu P7～Cu P9）derived from water-soluble porphyrin have been synthesised and evaluated for their biological activity.Three complexes all exhibited potent binding affinity against ct-DNA,especially,Cu P8 interacted with ct-DNA stronger than Cu P7 and Cu P9.MTT assay indicated that the complexation improved the anticancer activity of the ligand and reduced side effects on normal cells significantly,in particular,Cu P8 exhibited strongest cytotoxicity to H-1975 cells,possibly due to its excellent planar properties and small molecular size.Besides,cell absorption experiments showed that the four tested cancer cells had good absorption of complexes,which was attributed to the good water solubility of cationic porphyrins.Moreover,fluorescence imaging experimental results indicated that Cu P8 could induce the H-1975 cells apoptosis,the possible mechanism of Cu P8 induced of H-1975 cells apoptosis mainly by accumulated cells in the G2 phase.