【作者】 王强；

【导师】 汪志勇；

【作者基本信息】 中国科学技术大学 ， 有机化学， 2013， 博士

【摘要】 本论文包括两方面的研究,即α-氨基酸的脱羧环化反应研究和靶向于PCAF bromodomain的小分子抑制剂研究。PART Ⅰ:α-氨基酸的脱羧环化反应研究天然α-氨基酸广泛存在于自然界,是多肽以及蛋白质和很多活性分子的基本组成成分。由于天然α-氨基酸十分易得,价格低廉,而且是绿色无毒的合成原料。鉴于天然α-氨基酸的重要性和众多优点,有机化学家已经对其进行了大量的研究。其中包括天然α-氨基酸作为催化剂催化的不对称反应,和用其作为原料合成有用的分子。但是更多的研究主要集中在对天然α-氨基酸进行修饰过后作为配体、有机小分了催化剂、常规的反应底物等。而直接采用天然α-氨基酸作为起始原料通过脱羧活化合成共轭氮杂环却很少有报道。本部分的研究集中在采用天然α-氨基酸作为起始原料和氮源,通过非金属催化脱羧活化实现两大类氮杂环——吡啶类和咪唑[1,5-a]并环类的合成。PART Ⅱ:靶向于PCAF bromodomain的小分子抑制剂研究。HIV感染引起的艾滋病是当今医学界尚未攻克的难题。由于HIV具有很强的变异性,针对于其生命周期的蛋白以及酶类的药物很难起到很好的效果。近年来,相关文献报道PCAF bromodomain作为宿主蛋白在HIV的生命周期——转录过程中起到至关重要的作用。PCAF bromodomain通过与HIV Tat选择性的结合和解离来调控HIV在宿主细胞中的转录。我课题组和美国西奈山医学院合作报道了靶向于PCAF bromodomain的小分子抑制剂,并提出了PCAF bromodomain作为艾滋病治疗的新靶点的设想。为了进一步证明PCAF bromodomain的靶点可行性,我们研究了靶向于PCAF bromodomain的小分子抑制剂的细胞水平的抗HIV-1的实验。并对小分子抑制剂在分子水平和细胞水平的构效关系以及相关性给予了初步分析。结果得出N1(芳基)-1,3-丙二胺类化合物具有很好的抗HIV-1的活性,也进一步证实了PCAF bromodomain作为HIV-1靶点的可行性。为了进一步提高筛选效率,我们又发展了新的荧光偏振筛选方法,应用于PCAF bromodomain小分子抑制剂的筛选,并发展了一类新的先导化合物——吡啶氮氧类化合物。通过衍生和活性测试,结果显示此类分子在分子水平具有很好的抗PCAF bromodomain与Tat-AcK50结合的活性。更多还原

【Abstract】 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.更多还原