Study On The Decarboxylative Cyclization Reactions Of α-amino Acids&Study On Inhibitors Targeting PCAF Bromodomain

This thesis can be divided into two parts, one part focuses on the decarboxylative cyclization reactions of a-amino acids, the other part focuses on the studies of inhibitors targeting PCAF bromodomian.PART I:Decarboxylative cyclization reactions of a-amino acids.Natural a-amino acids as the elementary element of peptides and proteins extensively exist in the nature. a-Amino acids are readily accessible and the price of them are relatively cheaper than other common reagents. More importantly, they are green and non-toxic reagents for organic synthesis. Duing to their advantages and importance, organic chemists around the world have performed many related researches. For instance, a-Amino acids can be used as catalysts in asymmetric reactions, as well as used as substrates to develop new organic reactions. However, most previous researches focused on their catalytic application in asymmetric reactions, in which a-amino acids and their derivatives were employed as chiral ligands and organo-catalysis. Decarboxylative coupling reactions of aromatic carboxylate have developed a lot in recent years, while the decarboxylative coupling reactions of a-amino acids are still not fully discovered, especially for n-conjugation systems construction from primary a-amino acids. In this part, we made use of the active intermediates formed from a-amino acids decarboxylation and developed two new coupling reactions and successfully obtained two kinds of N-heterocycles pyridines and imidazole[1,5-a]cycles.PART II:Studies on inhibitors targeting PCAF bromodomain HIV caused AIDS is still an incurable disease by now. HIV mutates to evolve and enable HIV to show resistance to the common drugs that target the proteins and enzymes expressed by HIV genes. Obviously, common drugs cannot provide desired therapeutic results. In recent years, host cell protein PCAF bromodomain has been defined as an important molecular switch for HIV transcription. PCAF bromodomain regulates the HIV-transcription by its association with HIV-Tat. Previously, our group cooperated with M-M Zhou group and developed inhibitors targeting PCAF bromodomain. Also, we firstly suggested PCAF bromodomain as a new potential target for AIDS therapy. To further validate the feasibility of PCAF bromodomain as a target for AIDS therapy, we conducted an anti-HIV assay on cellular level. Based on the results and previous report, the primary SAR on cellular level was obtained. Also, the correlationship of molecular level activity and cellular level activity was analyzed. Results presented that N1-(2-nitrophenyl)propane-1,3-diaminederivatives had good anti-HIV-1activities and the activities were correlated very well with the molecular level assay results reported previously. This indicated that these compounds probably targeted PCAF bromodomain and provided anti-HIV-1activities. As a conclusion of the analysis, PCAF bromodomain probably could be a target for anti-HIV drugs. On the other hand, to increase the screening efficience, we developed a screening and evaluation method based on polarization fluorescence. Also, another new leading compound2-(3-aminopropylamino)-5-methylpyridine1-oxide was discovered. From the activity-evaluation results on molecular level, it was found that some of this kind of compounds showed good activities against PCAF bromodomain/Tat AcK-50association.