| Diabetes mellitus?DM?which is the high blood glucose,hyperlipidemia and insulin resistance,is one of the most important global public–health problems.DM has been identified as one of the three diseases most difficult to cure by the world health organization.Despite lifestyle modification and pharmacotherapy,the glycemic control of patients with type 2 diabetes mellitus?T2DM?aggravates over time mainly due to the continuous deterioration of pancreatic?-cell function.In this respect,it is very difficult to obtain durable glycemic control for quite a long time with current drug treatment options.Therefore,the development of some new organic chromium???complex drugs or chromium???functional supplements on T2DM is still research hotspot,and ligand plays a significant role in improving the bioactivity of chromium???complexes.In this thesis,10 new chromium???complexes with the series of salicylic acid and best-selling oral glucose-lowering drugs metformin and phenformin as ligand were synthesized on the basis of the original research group,and their structures were characterized;The physical chemistry properties were studied;the binding interaction of the chromium complexes and glucagon was carried out.The biological activity and toxicity of chromium???complexes were explored preliminarily.The main contents are as follows:???Preparation and characterization of chromium???complexesIn this paper,the conventional solution synthesis method was chosen mainly.The salicylic acid and its derivatives were selected to reacted with chromium???to synthesize seven new chromium???complexes such as:[Cr3O?SA?7·2CH3OH]·3CH3OH,[Cr3O?SA?7·2H2O],[Cr?3-CH3-SA?·TETA]·Cl,[Cr4Na6?3-CH3-SA?8·2OH-·4C2H5OH·14H2O]·2H2O[Cr?5-Cl-SA?·4H2O]·Cl,[Cr?5-Br-SA?·4H2O]·Cl and[Cr?4-CH3-SA?·4H2O]·Cl2;The biguanides drugs were selected to reacted with chromium???to synthesize three new chromium???complexes such as[Cr?Met?3],[Cr?dipic?2]·Met and[Cr?Phf?3]·Cl3,which were fully characterized by elemental analysis?EA?,electrospray ionization–mass spectrometry?ESI–MS?,nuclear magnetic resonance?NMR?,infrared?IR?,UV–Vis absorption,fluorescence spectra,and single crystal X-ray diffraction,et al.???Physics-chemistry properties of chromium???complexesThe stability and resistance to oxidation under different tempreture,different pH environments and irradiation condition of the complexes were discussed by means of UV-Vis absorption spectra.Overall,complex?1?has good stability among the salicylic acid series complexes,and it is not easy to be oxidized;Among biguanide series complexes,complex?8?has good stability and are not yet easily oxidized.The thermal decomposition of solid complexes were studied using TG-TDA method,and the thermal decomposition temperature of the remaining complexes is higher than 100 oC except complex?3?,and this is advantageous to the preservation and storage of complexes.The initial structures of the four complexes were optimized by Gaussian 09 package with density functional calculation,and the HOMO and LUMO and Eg was also discussed.The results showed that the theory structures of optimization results accord with crystal structure or the structure inferred are very good,and the HOMO and LUMO energy level value and Eg is also in keeping with the experimental results.Electrochemical properties of complexes?8?and?9?were studied using cyclic voltammetry,and the results showed that the complexes in solution has good redox properties;The complexes?8?and?9?should be also occured reversible redox reaction in the organisms,and this may be mainly due to the polyvalent state of Cr itself.Additionally,the magnetic properties of complexes?1?and?2?were also studied,and the plots of the experimental data in the form of?MT?2300 K?proved Cr???…Cr???of two trinuclear oxo-centered Cr???assemblies are antiferromagnetic exchange,which is antiferromagnetic and consistent with other similar structures.???Binding interaction of the chromium???complexes and glucagonGlucagon is a hormone secreted by pancreatic islets?-cells,and the effect of glucagon is in contrast to insulin.It is composed of 29 amino acids,which contain 1tryptophan and 2 tyrosine residues,with endogenous fluorescence.If glucagon secretes too much,there will be hyperglycemia.So inhibiting the excess secretion of glucagon will prevent the onset of T2DM.Under physiological conditions,the binding interaction of CrCl3·6H2O,complex?1?,?8?and?10?with glucagon was studied by fluorescence spectroscopy.The preliminary experiments showed that:?i?The fluorescence quenching mechanism of four chromium compounds on glucagon was a static quenching caused by the formation of glucagon complex.?ii?The binding constants of the four compounds to glucagon are:0.96×105?CrCl3·6H2O?,1.79×105?1?,1.73×105?8?and 1.29×105?10?L·mol-1(Kcomplex?105 L mol-1).Thus,it is proved that the binding forces of complexes with glucagon is stronger and the order is:[Cr3O?SA?7·2H2O]?[CrMet]?[CrPhf]?[CrCl3].?iii?The preliminary inference is that the combination ratio is 2:1.???The biological activity of chromium???complexesThe biological activity of complexes is an important concern for researchers in the field of biological inorganic.In this paper,STZ–induced diabetic model mice were treated for the administration of complex[Cr3O?SA?7·2H2O],[Cr?Met?3],[Cr?dipic?2]·Met and[Cr?Phf?3]by oral gavage for 4,8 and 12 weeks,and alters of BW,FBG,FINS,TC,TG,HDL and LDL levels of biological activity were tested in each cycle.These results showed that[Cr3O?SA?7·2H2O],[Cr?Met?3]and[Cr?dipic?2]·Met have significantly hypoglycemic lipid-lowering biological activity,and this is mainly due to synergistic effect of Cr???and ligands.???Preliminary study on toxicity of chromium???complexesThe safety of complexes[Cr3O?SA?7·2H2O],[Cr?Met?3],[Cr?dipic?2]·Met and[Cr?Phf?3]were evaluated by MTT test,oral acute and chronic toxicity experiment.The experimental results showed that the complex[Cr3O?SA?7·2H2O],[Cr?Met?3]and[Cr?dipic?2]·Met have good biocompatibility,low toxicity to cells and non-toxic and safe for health mice.In summary,the biological synergistic effect of metal Cr???and active ligands were analyzed comprehensively from the perspective of bioinorganic chemistry by crystal structure of complexes,interaction of complexes with glucagon,biological activity and toxicity.We believe that these original research conclusions can provide some scientific basis and academic value for the chromium chemical researches. |
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