Synthesis,DNA Binding And Anticancer Activities Of Corroles And Their Metal Complexes

Cancer is one of the world's three major killers that threaten human health,and the second leading cause of death only to cardiovascular and cerebrovascular disease.The mortality rate of cancer is the highest of the major diseases.How to reduce mortality and even cure cancer is one of the biggest challenges in front of scientists in the world.Traditional treatment shave serious side effects,drug resistance,and little effect on advanced cancer,therefore,the main areas of anti-cancer research are to design and synthesis of highly toxicity and low side effects drugs or to find new treatments.Photodynamic therapy(PDT)is more controllable and has the potential to selectively destroy malignant cells while sparing the normal tissues.PDT involves the combination of visible light,oxygen and a photosensitizer.The dual selectivity of PDT is produced by both a preferential uptake of the photosensitizer by the diseased tissue and the ability to confine activation of the photosensitizer to this diseased tissue by restricting the illumination to that specific region.The main photosensitizers in PDT are porphyrin compounds.Pharmacologicala scorbate can selectively inhibit or kill tumor cells while sparing the normal tissues.Catalytic manganese porphyrins(MnP)would increase AscH-oxidation rates,thereby increasing H2O2 fluxes and significantly increas the cytotoxicity of ascorbic acid to tumor cells.Corroles are composed of four pyrrole and three methylene 18-? conjugated macrocyclic compounds belonging to the porphyrinoid family.They can be used in tumor imaging,diagnosis and as new type of photosensitizers in PDT.Manganese porphyrins can significantly increas the cytotoxicity of ascorbic acid to tumor cells,but similar study don't find by manganese corroles.So,in this dissertation,pyridyl corroles 1,2,3,polyhydroxy corrole 4 and its gallium complex 4-Ga,manganese complex 4-Mn are synthesized.And the research of their interaction with DNA and anti-tumor activity are shown in below:Firstly,four corrole compounds,5,10,15-tris(4-pyridyl)corrole(1),10-(pentafluorophenyl)-5,15-bis(4-pyridyl)corrole(2),10-(4-pyridyl)-5,15-bis(pentafluorophenyl)corrole(3),5,10,15-tris(4-(2-hydroxyethyl)amino-2,3,5,6-tetrafluorophenyl)corrole(4)and its metal complexes 4-Ga,4-Mn are synthesized.And their structures are characterized by UV-Vis spectroscopy,high resolution mass spectrometry and NMR.Secondly,the interaction modes of these corroles with DNA are studied by UV-spectroscopy,fluorescence spectroscopy and viscosity assay.The experimental results show that the DNA-binding affinities of 1,2 and 3 follow the order 1 > 2 > 3.Corroles 4,4-Ga and 4-Mn interact with DNA through an outside binding mode.The ability of corroles to break DNA is studied by agarose gel electrophoresis.The results show that corroles 1,2,3,4 and 4-Ga can induce DNA photocleavage effectively,and the cleavage is related to the production of 1O2.In the presence of 1 mM vitamin C,corrole 4-Mn can induce DNA cleavage effectively,and the cleavage mechanism is related to the production of the high activity of hydroxyl radicals(·OH).Thirdly,the potential application of the corroles in the treatment of tumor is studied by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide(MTT)assay,cell morphology,cell uptake,ROS detection,mitochondrial membrane potential change,apoptosis detection,cell cycle detection and single cell gel electrophoresis.The results show that corroles 1,2,3,4 and 4-Ga can be used as photosensitizers in PDT.The preliminary study of the anti-tumor mechanism is that the generation of reactive oxygen species causes the mitochondrial membrane changes and nuclear damage,and finally induced apoptosis led to tumor cell death.Combined with vitamin C,4-Mn can be used as antineoplastic agents.The preliminary study of the anti-tumor mechanism is that the generation of reactive oxygen specise(ROS)causes the mitochondrial membrane changes and nuclear damage,arrests cell cycle in G0/G1 phase and finally induces apoptosis led to tumor cell death.Fourthly,the results of pyridyl corroles 1,2 and 3 comparing with each other in biological activity show that the structures of corroles have great effect on their interaction with DNA,DNA photocleavage and anticaccer activity.