Cu^?N₂O₂ Multi-functional SOD Mimics:Synthesis,Activities In Vitro And Biological Models,Theoretical Calculations

Superoxide dismutase ?SOD? can catalyze the dismutation of superoxide radical anion, and SOD acts as an important antioxidant defense against various pathological conditions. But as a protein, SOD has several shortcomings in clinical application. To circumvent such limitations, much effort has gone into synthesis and property investigation of low molecular weight SOD mimics. Among the related studies, the Cu^?N₂O₂ structural motif has received tremendous attention, since it mimics the active site structure of Cu, Zn-SOD, and the complexes with this structural motif ?Cu^?N₂O₂ complexes? exert potent SOD activity. Furthermore, it is reported that some Cu^?N₂O₂ SOD mimics also exhibit the catecholase activity.Although many potent Cu^?N₂O₂ enzyme mimics have been prepared, two important disadvantages exist in this research field:?1? The structure-activity relationship analysis of these mimics is relatively less, while the investigation of the structure-activity relationship plays an important guiding role in the studies of enzyme mimics. ?2? Studies of Cu^?N₂O₂ mimics usually stagnate in the assessment of their biological activities in vitro. However, the main research purpose of enzyme mimics is the application in vivo, and there are many differences between complexes' biological activities in vitro and in vivo/cell. Therefore, it is of importance to investigate the performance of complexes in biological models for the evaluation of their enzyme-mimetic properties and application potential in biology and medicine science.As the N-heterocyclic structure, tetrazines have unique skeleton and chemical/physical properties, and stable complexes can be obtained utilizing tetrazines as the ligand. Thus, tetrazines have a wide range of applications in the synthesis of muti-functional complexes.This work focuses on design and synthesis of multi-functional SOD mimics, their property investigation, structure-activity relationship analysis and application research in biological models.1. Based on the biomimetic synthesis strategy, three new mixed ligand Cu^?N₂O₂ complexes, namely, [Cu??2-A-6-MBT?2?m-NB?2] ?1?, [Cu??2-ABT?2?m-NB?2] ?2? and [Cu??2-ABT?2?o-NB?2] ?3? ?2-A-6-MBT=2-amino-6-methoxybenzothiazole, m-NB= m-nitrobenzoate,2-ABT=2-aminobenzothiazole, and o-NB=o-nitrobenzoate?, have been prepared by utilizing bioactive molecules,2-amino benzothiazole derivatives and nitro benzoic acid derivatives as ligands. Their structures were determined by X-ray crystallography studies and spectral methods.2. The property investigation reveals that these complexes exhibited the potent superoxide dismutase ?SOD? activity and satisfactory catecholase activity.3. On the basis of the experimental data and computational studies, the structure-activity relationship for these complexes was investigated. The results reveal that electron-accepting abilities of these complexes and coordination geometries have significant effects on the SOD activity and catecholase activity.4. Then, it is found that 1 and 2 exerted potent intracellular antioxidant capacity in the model of H2O2-induced oxidative stress based on HeLa cervical cancer cells, which were screened out by the cytotoxicity assays of different kinds of cells. Furthermore,1-3 showed the favorable biocompatibility in two different biological models:Saccharomyces cerevisiae and human vascular endothelial cells. These biological experimental data are indicative of the promising application potential of these complexes in biology and pharmacology.Above work has been reported ?Inorganic Chemistry 2014,53,13019-13030?.5. Cooperating with other member of our group, author prepared 223,6-disubstituted-1, 2,4,5-tetrazines by S-induced reaction of aromatic nitriles with hydrazine hydrate under thermal conditions. And among these tetrazines,18 compounds are unprecedented. These obtained 3,6-disubstituted-1,2,4,5-tetrazines are expected to prepare the novel SOD mimics with various biological activities and promising application potential in subsequent work.This work has also been reported ?RSC Advances 2015,5,12277-12286?.