Studies On Design,Synthesis And Application On The Binding Of Benzimidazole Rare Earth Complexes With Bovine Serum Albumin

Organic compounds containing benzimidazole groups are widely used in drug design.The N atom on the conjugated benzimidazole group has a lone pair of electrons,which makes benzimidazole compounds are excellent organic ligands.Rare earths possess abundant energy levels and special 4f electronic transitions.They exhibit unique luminescence properties.A series of mono-and binary complexes are obtained by coordination of benzimidazole compounds with rare earth ions,or the coordination of benzimidazole compounds,o-phenanthroline and rare earth ions in different ratios.These complexes may be used in the synthesis of anti-tumor drugs.The design and synthesis of benzimidazole rare earth compounds is a research hotspot in coordination chemistry,medicinal chemistry,organic chemistry and other related fields.In this thesis,four organic compounds containing benzimidazole groups have been synthesized.They are 4-（1H-benzimidazole-2-oxo）-oxbutyric acid（L₁）,3,5-bis（2-benzimidazolyl）pyridine（L₂）,2,2-（1,3-phenyl）bis[1H-benzimidazole]（L₃）,2-（4-hydroxyphenyl）benzimidazole（L₄）.L₁,L₂,L₃coordinate with europium,terbium,and samarium,respectively.Nine complexes are obtained.L₁,L₂,L₃and o-phenanthroline coordinate with europium,terbium,and samarium in different proportions.Six binary complexes are obtained.The synthesized complexes are characterized by elemental analysis,ultraviolet spectrum,infrared spectrum,fluorescence spectrum,thermogravimetric analysis.The binding interaction of benzimidazole compounds,rare earth complexes with bovine serum albumin（BSA）are investigated by fluorescence spectra,UV-vis spectra,respectively.The main contents are as follows:1.Synthesis of benzimidazole compounds.Using o-phenylenediamine andα-ketoglutaric acid as raw materials,the compound 4-（1H-benzimidazole-2-oxo）-oxbutyric acid（L₁）is obtained.Ortho-phenylenediamine mixed with 3,5-pyridinedicarboxylic acid and isophthalic acid in a ratio of 2:1,respectively,catalyzed by polyphosphoric acid（PPA）to close the ring.and 3,5-bis（2-benzimidazolyl）pyridine（L₂）,2,2′-（1,3-phenyl）bis[1H-benzimidazole]（L₃）are obtained,2-（4-hydroxyphenyl）benzimidazole（L₄）is obtained by the reaction of p-hydroxybenzaldehyde and o-phenylenediamine.The synthesized benzimidazole compounds are characterized by nuclear magnetic resonance,ultraviolet and infrared spectrum.2.Synthesis and characterization of rare earth complexes.Synthesis and characterization of rare earth complexes.Nine complexes are obtained by coordination L₁,L₂,L₃with europium,terbium,and samarium,respectively.They are Eu（L₁）₂Cl₆·1.5C₂H₅OH（Eu（L₁）₂）,Tb（L₁）₂Cl₃·2.5C₂H₅OH（Tb（L₁）₂）,Sm（L₁）₂Cl₃·4C₂H₅OH（Sm（L₁）₂）,Eu₂L₂Cl₆·3.5C₂H₅OH·5H₂O（Eu₂L₂）,Tb₂L₂Cl₃·3C₂H₅OH·6H₂O（Tb₂L₂）,Sm₂L₂Cl₃·5C₂H₅OH·6H₂O（Sm₂L₂）,Eu（L₃）₂Cl₆·4.5C₂H₅OH·7H₂O（Eu（L₃）₂）,Tb（L₃）₂Cl₃·5.5C₂H₅OH·7H₂O（Tb（L₃）₂）,Sm（L₃）₂Cl₃·6.5CH₃OH·7H₂O（Sm（L₃）₂）.Six binary complexes are obtained by coordination of compounds L₁,L₂,L₃,o-phenanthroline with europium,terbium,and samarium in different ratios.They are(Eu₂（phen）₃L₁·3H₂O,Tb₂（phen）₃L₁·5H₂O,Sm₂（phen）₃L₁·7H₂O,Eu₂（phen）₃L₃·6H₂O,Tb₂（phen）₃L₃·7H₂O,Sm₂（phen）₃L₃·7H₂O.The complexes are characterized by infrared,ultraviolet,fluorescence spectra.The calculation results show that the synthesized rare earth c omplex has good luminescence properties.3.The interaction between benzimidazole compounds,rare earth complexes and bovine serum albumin（BSA）.The binding interaction of L₁,L₂,L₃,and rare earth complexes with BSA are investigated by fluorescence spectra and UV-vis spectra,respectively.The binding constant Ka,number of binding sites n,and thermodynamic parametersΔH,ΔS andΔG are calculated.According to the theory of non-radiative transfer,the distance r between the quencher and BSA is calculated.The results show that the quenching method of the quencher and BSA is static quenching,the interaction distance r<7nm,0.5R₀<r<1.5R₀.The thermodynamic parameters of the interaction between the quencher and BSAΔG<0,which shows that the interaction between them is spontaneous.The interaction between L₂,L₃,Eu₂L₂,Eu（L₃）₂,Tb₂（phen）₃L₃and BSA is electrostatic.The interaction between L₄,Tb₂L₂,Sm₂（phen）₃L₃and BSA is hydrogen bonding and van der Waals force.The binding force of Tb₂L₂、Sm₂L₂、Sm（L₃）₂,Eu₂（phen）₃L₁,Tb₂（phen）₃L₁,Sm₂（phen）₃L₁,Eu₂（phen）₃L₃and BSA is hydrophobic.In summary,there are van der Waals forces,hydrogen bonds,electrostatic interactions or hydrophobicity between benzimidazoles and their rare earth complexes and BSA,which provide a practical basis for the application of benzimidazoles in drug development.