Design And Synthesis Of Anticancer Agent Based On Pyruvate Dehydrogenase Kinase Target

It is well known that cancer is one of the most common human diseases. Drug therapy is the main strategy to advanced cancers. However, drugs kill the normal cells while taking effect on the tumor cells, which cause massive side effects. New study indicates that inhibition of Pyruvate dehydrogenase kinase can induce the apoptosis of cancer cells and has little effect on normal ones. Our study focuses on the inhibition of Pyruvate dehydrogenase kinase on protein level and gene levels. The main results are as follows:A series of N-phenyl-α-trifluoromethylalaninamide derivatives and N-aryl-2-hydroxy-2-trifluoromethylpropionamide derivatives, which are two types of new potential PDK inhibitors, were synthesized and their anticancer activities were evaluated on KB-3-1, H460 and A549 cells. The N-aryl-2-hydroxy-2-trifluoromethylpropionamide derivatives displayed excellent anticancer activities on all these three kinds of cancer cells. Compound 21e is the best one, with the IC₅0 14.72μM, 8.2μM, 19.82μM respectively and its anticancer activity is about 200 times higher than DCA. As a result, 21e can be a leading compound for further structural optimization.In our study, 3′,5′-dithio-2′-deoxyuridine was synthesized by using 2′-deoxyuridine as starting material, 3′,5′-dithio-2′-deoxycytidine was synthesized by using 2′-deoxycytidine as starting material, 3′,5′-dithio-2′-deoxyguanosine was synthesized using guanosine as starting material. Meanwhile, all the five kinds of 3′,5′-dithio-2′-deoxynucleosides were prepared in large scale, which will be used for the synthesis of dithio-oligodeoxynucleosides.A new and efficient method for the stereo-selective preparation of N-arylglycosylamines via crystallization induced diastereomer stereoselective synthesis was developed. Single crystal X-ray diffraction method was used to study the reaction mechanism, while the result showed that stereo-selectivity was achieved through the formation of crystals. Aromatic amines react with unprotected monosaccharides in water, specially configurational N-Arylglycosylamines will form crystals through intermolecular hydrogen bonds. The crystals were filtered to get special configurational N-Arylglycosylamines. N-arly-α-D-ribopyranosylamine derivatives, N-arly-2-deoxy-α-D-ribopyranosylamine derivatives and N-arly-2-acetamido-2-deoxy-β-D-glucopyranosylamine derivatives were synthesized by using this method.