Hydroxyl Corrole And Its Metal Complexes: DNA-binding And Antitumor Activity

Cancer has been recognized as an intractable disease since the beginning of recorded time.Today,in spite of dramatic advances in biology and medicine,cancer incidence continues to increase and has reached epidemic proportions,it is urgent to develop new and efficient anticancer drugs.The genetic material of organisms is stored in the nucleotide sequence of deoxyribonucleic acid,and many anticancer drugs exhibit antitumor activity which maked DNA as target by destroying the tumor cells and affect gene expression,therefore,molecules with strong binding affinity to DNA can also be excellent chemotherapeutic agents.Thus,study on the interaction between compounds and DNA may also helpful to give more insight into their role in antitumor activity and design new efficient DNA-targeted drugs.Corrole is a member of porphyrin family macrocycle,whose potential anticancer application has greatly pushed the development of corrole-based bioinorganic chemistry.In this thesis,we report the synthesis of a new corrole,which bears two ethyl-hydroxyl groups and one hydroxyl group on periphery phenyl groups.Its gallium and manganese complexes were also prepared.Furthermore,the DNA interaction,photo-nuclease activity and in-vitro antitumor activity of corrole complexes were investigated.The main research contents as follows:(1)10-(4-hydroxyphenyl)-5,15-bis(4-(2-hydroxyethyl)amino-2,3,5,6-tetrafluorophenyl)corrole(1),its gallium(Ⅲ)complex(1-Ga)and manganese(Ⅲ)complex(1-Mn)were prepared.The compounds were characterized by UV-Vis,HR-MS,elemental analysis and NMR.(2)Interactions between corroles and calf thymus DNA were investigated by multiple spectroscopic methods(UV-vis spectra titration experiment,fluorescence titration experiment,circular dichroism titration experiment),viscosity experiments and molecular docking simulation.The results showed that both compounds could bind with DNA via outside binding mode,and gallium complex exhibited higher DNA binding affinity than freebase corrole.The results of molecular docking indicated that reveals that both corroles interact with DNA in major groove.(3)The photonuclease activities of 1 and 1-Ga were studied by agarose gel electrophoresis experiment.The result demonstrated that 1 and 1-Ga could be able to effectively cleave DNA after illumination.Singlet oxygen is the main reactive oxygen(ROS)species for 1,while singlet oxygen and hydroxyl radical were involved for 1-Ga photonuclease activity.(4)The cytotoxicity of 1 and 1-Ga against three tumor cells was detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide(MTT)assay.Both compounds demonstrated high photocytotoxic activity and might induce HepG2 cells apoptosis via ROSmediated mitochondrial pathways.Furthermore,1 and 1-Ga induced cell cycle arrest at S phase and G2/M phase,respectively.(5)Spectroscopic methods and hydrodynamics methods were used to study the binding mode of 1-Mn and calf thymus DNA.The results show that 1-Mn could bind with DNA via outside binding mode.Agarose gel electrophoresis experimental results showed that 1-Mn can effectively cleave DNA under the presence of ascorbic acid,and its fracture may involve hydroxyl radicals.