Design,Synthesis And Biological Applications Of Organic Conjugated Small Molecules

There are various small molecule active species in the organism,such as active oxygen species,reactive nitrogen species,and active sulfur species,which involved in many important physiological funcitons.Considering the high complexity of physiological processes,it is possible for two or even more of these active species to exert corporative effect on a complex transformation process.Fluorescent probes gradually show their unique advantages in the study of these active species.Therefore,while designing highly selective and highly sensitive fluorescent probe molecules for single active species is important,the development of mutually responsive fluorescent probes is essential for their research on molecular related regulation mechanism.In addition,the regulation of chemical intervention to some active species in vivo has positive significance in the treatment of cancer.Photodynamic therapy is a new type of cancer treatment that uses photosensitizer molecules to modulate the production of singlet oxygen in cancer cells under light excitation to achieve therapeutic goals.The design of novel,highly effective and highly targeted photosensitizers is very beneficial to the development of photodynamic therapy.In this regard,This dissertation consists of four arms listed as below:Arms 1.The "handle" molecule with a benzothiadiazole as the mother nucleus was used to study the interaction process of H2O2-H2S.Ultra-high-performance liquid chromatography showed that the response process was very efficient and eventually produced a clean fluorescent product.The study of the reaction mechanism found that the process can be rapidly completed by intramolecular redox reactions mediated by a thiyl radical-based reaction mechanism.In addition,targeting triarylphosphonium(TPP)-decorated salt modification to the "handle1" molecule,the first H2O2-H2S mutually responsive fluorescent prober was designed and synthesized.Fially,we achieved significant H2S-H2O2 mutual response in mitochondria.Arms 2.The above-mentioned "handle" molecule with H2O2-H2S interaction response was linked to rhodamine via an ethylnylene linkage.We obtained a kind of more sensitive response and higher fluorescence efficiency H2O2-H2S mutually responsive fluorescent probes.Theoretical calculations show that the fluorescence response of the probe is achieved through an efficient through bond energy transfer mechanism.The designed small probe molecules have many advantages such as large Stokes shift(170 nm),high response selectivity,and good biocompatibility.Laser confocal imaging observations revealed that the probe molecule also possesses high mitochondrial targeting and can simultaneously achieve an interactive fluorescence response to low concentrations of H2O2 and H2S molecules in the mitochondria.Arms 3.A novel hypochlorous acid fluorescent probe based on the hydrolysis of S-alkyl thiocarbamate was designed and synthesized.Since possessing a S-alkyl thiocarbamate locked dihydromethylene blue structure,the probe molecule itself has no near-infrared absorption and emission.When it reacts with hypochlorous acid,the thioester bond undergoes oxidative hydrolysis and methylene blue is released.The entire process exhibits up to 1700-fold increase in fluorescence response.In addition,the probe molecules exhibit very excellent selectivity.In addition to being free from other reactive oxygen species,reactive nitrogen species,amino acids,sulfhydryl compounds,and ions,which are commonly found in vivo,the probe molecules also show strong inertness to transition metal ions such as Hg2+,Ag+,and Pb2+.In vitro imaging experiments also showed that the designed probe molecules showed high fluorescence response to exogenous or endogenous hypochlorous acid in cells.Arms 4.Based on the chemical intervention regulation to intracellular singlet oxygen,a novel triarylphosphonium(TPP)-decorated DAD-type conjugated oligomer photosensitizer molecule was designed and synthesized,and successfully applied to mitochondrial targeted photodynamic therapy.The photosensitizer molecule has better water solubility and higher singlet oxygen quantum yield(0.64).At the same time,we achieved this photosensitizer which indicated localization in mitochondria under confocal fluorescence microscope and light-induced generation of reactive oxygen species(ROS).In the cytotoxicity test,the molecule was found to exhibit very low dark toxicity,contrary to normal oxygen concentration and hypoxia(5%O2),at a very low optical power(16 mW/cm2)for 3-5 minutes.It can kill up to 95%of the cell killing ability.In addition,photosensitizer molecules also exhibited good two-photon-imaging and photodynamic effects.These outstanding effects also indicated that this type of photosensitizer has broad application prospects.