DNA Binding And Hsa Interaction Of Water-Soluble Carboxyl And Pyridyl Corrole

DNA is the main intracellular target of most anti-cancer and antiviral agents, and HSA is the principal extracellular carrier protein in blood. Research on the DNA and HSA interaction with small molecule is very important for understanding the DNA structure and function, as well as the desige of new drugs design. Corrole chemistry is attracting increasing interests in recent years owing to the unique structure and novel photophysical properties. The synthesis of water-soluble corrole provides new opportunities in the field of biochemistry. Excet for platinum, gallium is the second metal which can be used to treat cancer. Gallium complexes have good cell penetration and anticancer activity. In order to further investigate the potential application of water-soluble corrole in biochemistry field, this thesis focused on the DNA binding, HSA interaction and nuclease activity of three water-soluble corrole, the main research contents are as follows:1. 5, 10, 15-tris(4-carboxyphenyl) corrole(2) was synthesized and characterized by UV-Vis, MS, NMR spectra and elemental analysis. The DNA binding property of 2 was studied by UV-Vis, fluorescence and circular dichroism spectroscopic methods, and viscosity measurements. Results revealed that 2 bound to DNA via outside mode with the binding constant of 1.05×105 M-1. Agarose gel electrophoresis experiments showed 2 display good photocleavage DNA activity and single oxygen is the reactive species. The in vitro inhibitory activities of 2 and 2-HSA complex against carcinoma of breast cells(MDA-MB-231), human hepatocellular carcinoma cells(Hep G2) and human cervical carcinoma cells(Hella) were evaluated by MTT. Low cytotoxicity of 2 indicated that 2 may be the potential fluorescence probe.2. The interaction between 2 or 5, 10, 15-tris[4-(N-methylpyridiniumyl)] corrole(3) and HSA was studied by UV-Vis, florescence, CD spectra and molecular docking simulation. The results showed that the interaction between them form the corrole-HSA complex, which statically quench the HSA fluorescence. 2 or 3 can bind to HSA with 2 having bigger binding constant for the hydrogen interaction. The site competition experiments using warfarin and ibuprofen as site marker displayed that 2 or 3 bind at both site I and site II of HSA, and prefer to site I. The binding distance calculated from Forster’s theory is 2-4 nm, indicating that the energy between HSA and corroles has occurred. What’s more, the interaction induced some changes of HSA conformation, mainly reduced the α-helix content.3. The interaction between 5, 10, 15-tris[4-(N-methylpyridiniumyl)] corrole gallium complex(3-Ga) was studied by the same spectroscopic methods and molecular docking simulation. Results also reflected that 3-Ga quench the fluorescence of HSA is a static process, and the binding constant is 2.82×104 M-1, binding distance is 3.342 nm. Thermodynamic parameters shown the interaction is mainly driven by hydrophobic and hydrogen binding force. Site marker competition experiment and molecular docking simulation indicates 3-Ga preferably bind to ibuprofen site II of HSA. Moreover, the interaction between 3-Ga and HSA disturbed the a-helix structure of HSA.