Construction And Evaluation Of Fluorescent Probes Of Mitochondrial-targeted 2-substituted Vinyl Quinolines For Aβ Protein And TTR Protein

Protein molecules can perform their correct physiological functions only when they are folded accurately to form the correct three-dimensional configuration.When the protein is misfolded and aggregate,amyloid fibers are formed,which can induce diseases with a variety of protein configurations,such as Alzheimer’s disease(AD),Transthyretin(TTR)amyloidosis,Parkinson’s disease(PK),Cystic fibrosis,cancer.Alzheimer’s disease is a well-known disease caused by protein aggregates,due to its complicated pathogenic mechanism,the pathogenesis is not well known.At present,single-target AD drugs cannot effectively improve the symptoms of AD.Therefore,development of multi-target therapeutic drugs has promising prospects in the treatment of AD.Fluorescent probes are widely used in the diagnosis of disease because of their non-damage,high specificity,high sensitivity,high resolution,low-toxicity,and in-situ imaging.With the deepening of research,the research of fluorescent probes for AD has gradually ocused on the development of multi-functional or multi-target probes.One of the hallmarks of AD is extracellular senile plaque(SP)formed of β-amyloid(Aβ).When the content of Aβ protein increases,it will cause many other related changes in the microenvironment.Studies have reported that when Aβ aggregates increase,it will cause the disorder of mitochondrial function and increase the viscosity of the mitochondrial environment.Mitochondrial metabolic dysfunction will be phagocytosed by lysosomes,and mitochondrial autophagy will occur.In the process of autophagy,mitochondria will be acidified.In addition to causing autophagy in mitochondria,Aβ aggregates are negatively correlated with the content of transthyretin tetramer protein.TTR tetramers can bind to Aβ protein to inhibit the toxic effect of Aβ protein on neurons.This thesis includes the following three parts:(1)Based on the 2-substituted vinyl quinoline skeleton,23 fluorescent probes were rationally designed and synthesized by introducing different electron donating groups or electron withdrawing groups.The evaluation results indicated that fluorescence signal of the azolidine substituted probe QM10 exhibited the most significant enhancement and largest quantum yield after incubated with Aβ aggregates.Moreover,it can be specifically located in mitochondria and monitor the viscosity changes in mitochondria.Then,the thiophene moiety was introduced into the π-conjugation to achieve the near-infrared emission,and six fluorescent probes were designed and synthesized.Then,by extension the ethylene double bond,the probe QM21 whose emission wavelength can reach the near-infrared before and after binding with the Aβ aggregates was designed and synthesized,and the emission wavelength reached 720 nm after binding with the Aβ aggregates.(2)Based on the 2-substituted vinyl quinoline skeleton,a fluorescent probe QM12 that can simultaneously image Aβ aggregates and mitochondrial p H was rationally synthesized by introducing 4-methylpiperazine.The probe can not only quantify the content of Aβ aggregates,but also detect the variation in mitochondrial p H.To the best of our known this is the first fluorescent probe reported so far that can simultaneously target Aβ aggregates and monitor mitochondrial p H changes.(3)Based on the hybrid structure of 6-dimethylaminoquinoline and 4-acetonitrile benzothiazole moiety,the first near-infrared fluorescent probe QCN-2 for TTR tetramer was rationally designed and synthesized.QCN-2 exhibited long emission wavelength of 694 nm and a large Stoke shift of 207 nm,and good affinity and selectivity with TTR tetramer.The probe can avoid the interference of autofluorescence of biomolecules owning to its NIR emission.