DNA Binding And HSA Interaction Of Water-soluble Transition Metal Corrole Complexes

The interaction studies between small molecules and DNA are gaining an increasinginterest owing to their important role for exploitation of biomedicines and anticancer drugs.Transition metal complexes have drawn considerable attention for their ability to interact withand cleave DNA. The synthesis and investigation of water-soluble corroles have broadenedthe usage of corrole in bioinorganic chemistry. Water-soluble cationic pyridyl-substitutedcorroles and sulfonated corroles have been reported to bind DNA and lead to DNA cleavage.In order to further investigate the properties of the interaction between corroles and DNA, thisthesis focused on the DNA binding and nuclease activity of different kinds of water-solubletransition metal corroles. The main contents of this thesis are as follows:Firstly,5,10,15-tris(4-carboxymethylphenyl)corrole and its manganese, iron and coppercomplexes were synthesized, then water-solubled corroles1-Mn,1-Fe and1-Cu wereobtained after hydrolysis;5,10,15-tris(4-pyridyl)corrole and its manganese, iron and coppercomplexes were synthesized, and water-solubled corroles2-Mn,2-Fe and2-Cu wereachieved after methylated; sulfonated manganese corrole3-Mn, iron corrole3-Fe and coppercorrole3-Cu were also synthesized. The synthesized corroles were characterized by UV-Vis,MS, NMR spectra and elemental analysis.Secondly, the interact mode between these synthesized water-soluble metal corroles werestudied by UV-Vis, fluorescence and circular dichroism spectroscopic methods, as well as byviscosity measurements. Results revealed that1-Mn,1-Fe,1-Cu,2-Mn,3-Fe and3-Cu bindto ct-DNA via outside binding mode.2-Fe interacts with CT-DNA in a difunctional way, i.e.,non-classical intercalation and outside groove binding with H aggregation, while2-Cu caninteract with CT-DNA via an intercalate mode. Besides, both the metal ion core and substituent of corrole affect the binding strength toward DNA, and the binding constantsfollows an order of iron corrole﹥copper corrole﹥manganese corrole, as well as cationiccorrole﹥carboxyl corrole﹥sulfnated corrole.Thirdly, the nuclease activities of these corroles were studied by agarose gelelectrophoresis experiments. The results showed that all the iron and manganese corrolesexhibited good catalytic activity in DNA oxidative cleavage in the presence of H2O2or tert-butyl hydroperoxide as oxidant, and tert-butyl hydroperoxide was performed to be a betteroxidant than H2O2in all cases. Moreover, the DNA cleavage ability of these corroles keeps tothe same order of their binding strength. Particularly, the DNA cleavage by1-Mn was a non-random double-stranded cleavage process. Inhibitor tests and UV-Vis studies suggested thatthe high-valent (oxo)-manganese or (oxo)-iron were the potent active intermediatesresponsible for the oxidative DNA scission, and singlet oxygen was also involved in the casesof2-Mn and2-Fe.Fourthly, the HSA interactions of the metal corroles were studied by using fluorescencespectral and UV-Vis spectral assay. The results indicated that all the corroles can interact withHSAA and their interact constant were in or near the order of10-5M-1, the number of bindingsites were approximately1, suggesting the strong interact of the corroles and the bindingmolar ratio is1:1. The binding site location investigation was carried out using warfarin andibuprofen as site marker fluorescence probe, the results revealed that all the studied metalcorroles bind to both warfarin site and ibuprofen site of HSA. The critical distance R0betweencorroles and HSA were calculated from Forster’s theory, and the obtained R0were1-3nm,indicating the energy transfer between the corroles and HSA have taken place.