Syntheses, Characterization And Anti-diabetic Activity Of Vanadium Complexes With Small Biological Molecules

Diabetes is currently one of the three major diseases that threaten human health (including cancer, cardiovascular disease). Vanadium compounds possess the physiological effects in improving the physical condition of diabetes and simulating physiological functions of insulin, and have a good prospect acting as a class of diabetes drugs. The vanadium compounds that has been used for the study of biological activity can be classified into two categories:the first, simple vanadium salts, such as NaVO3 and VOSO4; the second, vanadium compolexes. According to the type of ligands and the coordinated ways, the vanadium compolexes can be divided into vanadyl complex, vanadium peroxide complexes and vanadium hydroxylamido complexes. The vanadium hydroxylamido complexes are known to be one of the most promising candidates in the study of the insulin-mimetic activity of vanadium compounds. Because of the problem of the biocompatibility of inorganic vanadium compounds, so far, great attention has been paid to organic vanadium compolexes. In 1992, the first organic vanadium compolexes, Bis(maltolato)oxovanadium(BMOV), was synthesized and used to study the insulin-mimetic properties. Since then, various organic vanadium compolexes have been synthesized and has become a subject matter of study of insulin-mimetic in biological and pharmaceutical research. It is also a hot topics in the current bio-inorganic chemistry.We have selected small biological molecules as the second ligand, such as amino acids, organic acid and glucose to prepare eleven vanadium hydroxylamido complexes. In addition to the basic physical and chemical characterization, we have investigated their PTP1B inhibitory activity. Specific research works were described as follows.1. The preparation, characterization and properties of vanadium-amino acid-hydroxylamido complexes. Five vanadium hydroxylamido complexes with valine, leucine, phenylalanine, histidine and anthranilic acid as ligand was prepared in neutral aqueous solution, in which three complexes was suitable for X-ray diffraction of the single crystals. By elemental analysis, IR, UV-visible spectroscopy and X-ray photoelectron spectroscopy, the composition, molecular structure and electronic structure of these complexes were studed. Also we have analyzed their crystal structure and product purity by X-ray single diffraction and X-ray powder diffraction. The thermal decomposition, the electrochemical reaction activity and the stability in aqueous physiological buffer solution of these complexes were explored by Thermal analysis, Cyclic voltammetry experiments and Spectrophotometry. We have also made a determination of partition coefficient of the complexes in octanol-physiological buffer solution and a screening of the PTP1B inhibitory activity.The X-ray diffraction structural analysis results show that this series of the complexes crystal were compose of separated structural units by an extensive hydrogen bonding network or van der Waals forces. The different ligands have some influence on type of hydrogen bonds. Activity tests showed that the size of the alkyl side chains of amino acids of these complexes has some influences on the PTP1B inhibitory activity. This preliminary conclusion is a basis for further research and the establishment of the structure-activity relationship of vanadium complexes as insulin mimics.2. The preparation, characterization and properties of vanadium-carboxylic acid-hydroxylamido complexes.The five vanadium-oxalate(malonate)-hydroxylamido complexes have been obtained in neutral aqueous solution. The counter ions in this series of complexes are NH4+, K+, Na+ and Cs+. As same as that of vanadium-amino acid-hydroxylamido complexes, we have made a study on the composition, molecular structure, electronic structure, crystal structure, thermal stability, and stability in physiological buffer solution, the electrochemical properties in aqueous solution, the distribution characteristics in organic-aqueous solvent system and the inhibition of PTP1B activity of this series of complexes.X-ray diffraction experiments and structural analysis showed that different ligands and counter ions have a great impact on coordination mode of ligands and crystal structure of the complex. The carboxylic acid is one of ligands with a strong coordination ability. In this series of complexes, oxalic acid and malonic acid exhibit a variety of bonding mode, Potassium oxo-bis(hydroxylamido)oxalatovanadate is isomorphism with Cesiumoxo-bis(hydroxylamido)oxalatovanadate. Their novel three-dimensional network structures not only enrich the crystallography of oxalic acid on the coordination modes, but also have an impact on activity of the complex. The crystal structure of Potassium and Sodium oxo-bis(hydroxylamido)malonatovanadate show that the counter ion affects the crystal structure and the inhibition of PTP1B activity of the complex. Most significantly, we have found that vanadium-carboxylic acid-hydroxylamido complexes were a class of compounds with stronger PTP1B inhibitory activity than that of vanadium-amino acid-hydroxylamido complexes. They are also better water-soluble and more promising as the lead compound in treatment of diabetes.3. The preparation, characterization and properties of vanadium-D-glucosamine-hydroxylamido complexes.The vanadium-D-glucosamine-hydroxylamido complexes is unique tetravalent vanadium compound in our works. Some valuable conclusions have been obtained by characterization and research on it. The activity test results show that vanadium-D-glucosamine-hydroxylamido complexes have some inhibitory activity on PTP1B and should be a promising new class of insulin mimics.