Design, Synthesis And Biological Activity Study Of Mitochondrial Targeted Small Molecule Antioxidant

Mitochondria are important organelles that generate reactive oxygen species(ROS)in eukaryotic cells.Dysregulation of ROS metabolism in mitochondria could cause oxidative damage to cells,which in turn leads to the occurrence and development of a series of diseases.Scientists have attempted to maintain cellular redox homeostasis and normalize mitochondrial function through antioxidants.Therefore,the study of antioxidants with mitochondrial targeting function has gradually become a research hotspot.Based on this,this paper synthesized five mitochondria-targeted antioxidants,and systematically studied the relationship between mitochondria-targeted carriers,antioxidants,compound structures and antioxidant properties.The main contents of this paper are as follows:Chapter 1: The research background and topic selection ideas of this paper were introduced.Chapter 2: BODIPY and F16 were selected as mitochondrial targeting groups,2,3-dimethyl-1,4 benzoquinone was used as antioxidant,and modified with flexible carbon chains to prepare fluorescent visual Mitochondria targeting antioxidants BDQ10 and F-Q10.The compounds were characterized by NMR and mass spectrometry.MTT experiments showed that BD-Q10 and F-Q10 had low cytotoxicity and good biocompatibility.Further use laser confocal to explore the cell imaging ability and mitochondrial colocalization ability of BD-Q10 and F-Q10,and found that the cell imaging effect is good,the shape is clear,there is bright fluorescence,and the mitochondrial colocalization is better.A series of in vitro antioxidant experiments showed that both BD-Q10 and F-Q10 had good antioxidant properties.Among them,the antioxidant capacity of F-Q10 is stronger than that of BD-Q10.The author further verified the above experimental results through theoretical calculations.found that the delocalized range of positive charges in the mitochondrial targeting vectors BODIPY and F16 is a key factor for the entry of antioxidants into mitochondria.The above research shows that we have synthesized two antioxidants with good biocompatibility,strong mitochondrial targeting ability,and fluorescent visualization function.Chapter 3: The mitochondrial targeting peptide was selected as the mitochondrial targeting group,and 2,3-dimethyl-1,4-benzoquinone was used as an antioxidant,which was coupled through aliphatic chains of different lengths to prepare two Novel mitochondria-targeted antioxidants CPP-Q10 and CPP-Q5.Characterization was carried out by mass spectrometry.MTT assay showed that its cytotoxicity was low.We conducted relevant in vitro antioxidant experiments,and commercialized SKQ1 was used as a control.The experimental results showed that the in vitro antioxidant performance of CPP-Q10 was greater than that of SKQ1 and CPP-Q5,which indicated that CPP-Q10 has become an excellent mitochondria-targeted antioxidant.potential and great commercial prospects.Chapter 4: The mitochondrial targeting peptide was selected as the mitochondrial targeting group,vitamin E succinate was selected as the antioxidant,and the VE antioxidant CPP-VE with mitochondrial targeting function is synthesized.MTT experiment showed that CPP-VE has low cytotoxicity and good biocompatibility.In order to further verify the distribution of CPP peptide in mitochondria,I used FITC as a fluorescent labeling group to couple CPP peptide to obtain CPP-FITC.Laser confocal experiments showed that the mitochondrial colocalization ability of CPPFITC was good,indicating that CPP peptide could enter and accumulate in mitochondria.The relevant in vitro antioxidant experiments of CPP-VE show that the antioxidant performance of CPP-VE is better than that of commercial vitamin E.This indicates that targeting vitamin E to mitochondria can achieve better antioxidant effects.Therefore,CPP-VE has the potential to become an excellent mitochondriatargeted antioxidant and has positive commercial application prospects.Chapter 5: Discussion and Conclusion.The in vitro antioxidant capacity of these five mitochondria-targeted antioxidants was compared and found: CPP-Q10≈CPPVE>SKQ1>VE>F-Q10>BD-Q10>CPP-Q5.During the analysis of drug structureeffect relationship,it was found that factors such as cation delocalization range and carbon chain length had a great influence on the antioxidant capacity of the compound.In the later stage,we will continue to conduct in-depth research on the structureactivity relationship of drugs,hoping to provide reference and reference for the development of new mitochondria-targeted antioxidant drugs.