Synthesis And Biological Activity Assay Of2-Aryl-Quinoline-4-Carboxylic Acid Derivatives

2-Aryl-quinoline-4-carboxylic acid-based compounds have various biological activities, such as antipyretic analgesic, anti-inflammatory, anti-oxidation, anti-tumor and anti-viral. For example. Cenchophin. was used as the antipyretic analgesic for the treatment of gout. Currently, the application of this agent combining with prednisolone is used to treat arthritis for animal. In the past two decades, a lot of research work have been performed the synthesis and pharmacological studies on2-aryl-quinoline-4-carboxylic acid derivatives. Especially in recent years.2-aryl-quinoline-4-carboxylic acid-based compounds have been reported as chemosensors due to their good fluorescence properties. These compounds could be used for recognize carbohydrates, catecholamines or other life-related substances.It was reported that2-phenylboronic acid-quinoline-4-carboxylic acid is a new water soluble boronic acid-based fluorescent sensor for carbohydrate. This sensor have the advantages such as significant fluorescence output after binding with carbohydrate and easily optimization for their derivatives.. In our previous studies, a series of diboronic acid based on the fluorescent reporter were synthesized and found one compound could recognize the oligosaccharide. In our recent studies, we found that low concentration of catechol can decrease the fluorescence intensity of this compound, which suggest that2-phenyl-quinoline-4-carboxylic acid could be used as catechol sensor without the interference of the carbohydrate. The detection limit of this compound in rabbit plasma was also resolved as the concentration of catechol, which resulted in a statistically significant decreasing in fluorescence intensity with a p-value<0.01compared with a blank control.As we knows, catecholamine derivatives, such as dopamine, L-DOPA and adrenaline, are widely existed in human bodies and exhibit various biological effects. Therefore, development of fluorescent sensors for catecholamine derivatives is very important especially for the studies on their monitoring in pathological studies. However,2-phenylboronic acid-quinoline-4-carboxylic acid has no selectivity on catechol and catecholamine derivatives. According to our previous result, the amidation of carboxyl group in this compound didn’t influence its binding affinity for catechol derivatives. In addition, the amino group in dopamine and L-DOPA could be used as second binding site for our fluorescent sensor. Therefore, a series of chemosensor were designed and synthesized based on the reporter of catechol and the different linker with carboxylic acid or boronic acid. Totally,47new compounds were synthesized, which include18target compounds identified by MS,’H-NMR,13C-NMR and HRMS. Preliminary studies showed that one compound,9d has stonger binding affinities and selectivies on L-DOPA compared with catechol and dopamine. These results indicated that the length of the linker of target compound has significant influence on the binding affinity and selectivity to L-DOPA. For example, compounds with the linker of one or three methylene units have no selectivity on catechol and catecholamine derivatives. While the linker extend to five methylene unit, the binding affinity and selectivity to L-DOPA could be increased. On the other hand, target compound7h shows the selectivity on dopamine with long emission wavelength for their fluorescence output, which could be helpful to find new long wavelength reporter for dopamine detection.The second part of this thesis focus on the development of HDAC inhibitors based on2-phenyl-quinoline-4-carboxylic acid. In our previous studies, a series of tetrahydroquinoline and thiadazole derivatives were developed as HDAC inhibitors. As the surface recognition region, thiadazole ring could be replaced by2-phenyl-quinoline according to our previous SAR studies. In our on-going work, different linker and zinc binding group were introduced to the2-phenyl-quinoline-4-carboxylic acid structure, which totally synthezied79new compounds including31new target compounds. All the target compounds were identified by ESI-MS,’H-NMR,13C-NMR or High Resolution Mass Spectrometry. The preliminary binding results showed that, compound5compunds have the IC50value less than1μM and compound22d showed potent HDACs inhibitory similar to SAHA. Further studies on HDACs subtype selectivities and antiproliferative activities are in progress.In summary, our research work on2-phenyl-quinoline-4-carboxylic acid deriatives showed that these series compounds could used as fluorescent reporter of catechol and HDAC inhibitors after structural modification. The2-phenylboronic acid-quinoline-4-carboxylic acid has the ability of fluorescence quench after addition of catechol derivatives. The structural modification on the4-carboxylic acid could be helpful to find selective fluorescent sensor for L-DOPA and dopamine. On the other hand, different linker and zinc binding group could be introduced to2-phenyl-quinoline-4-carboxamide derivatives, which could be used as lead compound to develop new HDAC inhibitors.