Design, Synthesis And Evaluation Of Small Moleculars As New Tools For Pharmic Research

This thesis mainly deals with three parts of work:1) the development and application of cadmium probe; 2) the design and study of HSA probe; 3) Synthesis and biological evaluation of novel aryl-2H-pryazole derivatives as potent non-purine xanthine oxidase inhibitors.Cadmium, one of the most toxic metals, is widely used in industry and agriculture. It is reported that cadmium can be absorbed and accumulated by plants and other organisms, which leads to environmental pollution and human diseases including cancers and neurodegenerative diseases. Therefore, developing a simple and fast method for Cd2+ quantification in vitro and in vivo is in great demand. In this work, NJ1Cd, was designed as a quinoline-based and 2-hydrazinopyridine-based ratiometric Cd2+ probe. NJ1Cd exhibited an emission peak at 515 nm without adding Cd2+, Cd2+ titration lead to the distinct emission red-shift from 515 nm to 570 nm. The emission ratio at 570 and 515 nm (F570/F515) increases upon the addition of an increasing amount of Cd2+. The titration experiment showed that the Cd2+ concentration and the florescence signal change ratios(F57o/Fsi5) exhibited a consistent linear correlation wihtin the 1 to 10 μM range with a limit of detection of 0.26 μM. The fluorescence responses of NJ1Cd to various representative metal ions were investigated, which showed a good selectivity for Cd2+. NJ1Cd can be potentially used to quantitatively detect Cd2+ concentration in 2 min. Finally, we performed the fluorescence imaging of NJ1Cd for detecting Cd2+ in living cells.Human serum albumin (HSA), with a normal concentration range between 35 and 50 g/L in blood plasma, is the most abundant protein in the circulatory systems. Levels of albumin in urine are normally below 30 mg/L, as the kidneys can prevent albumin from entering urine. However, the concentration of alumin increases when the filtering ability of the kidney is damaged, which induces many diseases. Therefore, the quantitative detection of alumin in urine has gained much importance in diagnosis and preventive medicine. We designed a fluorecent probe for detecting human serum albumin on the basis of its pseudo-esterase activity. HSA exhibits esterase-like activity and hydrolyzes drugs having an ester group. The designed probe, S1, has two ester groups so that can be hydrolyzed in principle. The hydrolyzed product of S1 would interact with amino acids of HSA, which can induce a fluorescence enhancement. S1 exhibited a weak fluorescence intensity at 539 nm without adding HSA, HSA titration lead to the distinct fluorescence increase at 539 nm. The emission ratio at 539 nm (F/F0) increases upon the addition of an increasing amount of HSA. The titration experiment showed that the HSA concentration and the fluorescence signal chang rations(F/F0) exhibited a consistant linear correlation within 1 to 10 μM range with a limit of detection of 0.72 μM.Xanthine oxidase (XO) is a key enzyme in the purine metabolic pathway. It catalyzes the oxidation of xanthine and hypoxanthine into uric acid. There is an overwhelming acceptance that XO serum levels are increased in various pathological states like hepatitis, inflammation, ischemia-reperfusion, cancer and aging. The inhibition of XO reduces the production of both uric acid and ROS, which can be used to treat gout and other related diseases. The purine analogs could induce life-threatening effects as XO inhibitors. We synthesized a series of aryl-2H-pyrazole derivatives were and evaluate the inhibitory activity against XO in vitro. Compound 19 showed the best inhibitory activity against XO (IC50=9.8 μM). Docking simulation of compound 19 into XO active site showed that 19 with THR354 and LYS256 form two H-bonds,19 with LYS256 form one cation-π bond.