To The Guideline Of Antihypertensive Drug Molecular Design, Synthesis And Spectral Properties Of Fluorescent Probes

At present, cardiovascular disease is one of the major diseases which cause the human toll.The key to the cure of cardiovascular disease is early detection, early diagnosis and earlytreatment. The fluorescence probe technique has some outstanding advantages such as highsensitivity, selectivity, real-time in situ detection and non-injury and so on. There is a goodprospect for the applications of the fluorescence probe technique in terms of diagnosis, timeresolution, mechanism study and trace detection.In this thesis, we regarded the anti-hypertensive drugs (betahistine, dibazole and losartan)with a good affinity to cardiovascular disease as target-oriented molecular, designed andsynthesized a series of fluorescent probe molecules. Then we studied their spectral properties andfluorescence imaging in cells, and evaluated their cytotoxic activities by MTT assay.(1) Six betahistine-oriented fluorescent probes with different fluorescent chromospheres andstructures were designed and synthesized. Spectroscopy studies have shown flexible linkers caneffectively reduced potential interaction between betahistine and fluorescent chromophores. Cellimaging experiments indicated fluorescent probes based on betahistine have good cellcompatibility and penetrating, and their fluorescence signals were mainly concentrated in thecytoplasmic region. In addition, the cytotoxicity of the series of compounds on Hela cells wereallowed within the range of the drug concentration, but the fluorescent drug probes with a flexiblechain exhibited the more cytotoxicity. The results showed that the introduction of flexible chainscan effectively reduce the influence of the fluorescent chromophore to betahistine activity.(2) Hydroxyl dibazol (DBZL-OH) and amino dibazol (DBZL-NH2) were synthesized bystructural modification of dibazole. The fluorescent probe molecules with flexible chains(DNSAca-O-DBZL, DNSAca-NH-DBZL,4-MNPAca-O-DBZ and4-MNPAca-NH-DBZL) weredesigned and synthesized based on these two drug molecules with different skeleton structure. Thespectral and cellular imaging results show that they have strong green fluorescence, and thefluorescent compounds based on amino Dibazol have more effective fluorescence imaging thehydroxyl Dibazol oriented fluorescent probes. Contemporaneously,4-MNPAca-O-DBZL and4-MNPAca-NH-DBZL have better stability and stronger fluorescence intensity, futher more theyhave taken on better cell imaging results and more easily to enter the cytoplasm. The cytotoxicityresults also show that the introduction of flexible chains can effectively reduce the influence of thefluorescent chromophore to betahistine activity.(3) Losartan reacted with4-MNPAcaOH by esterification to synthesize4-MNPAca-O-L. Thefluorescence spectra indicated that4-MNPAca-OL has a large stock displacement. Cell imaging experiments showed that losartan molecules are mainly distributed in the cytoplasmic region. Atthe same time, the cell toxicity experiments illustrated that4-MNPAca-OL has obvious toxicity tocells in concentrations greater than20μM.