基于炔酰胺叶立德捕捉的α，β-二氨基酸酯衍生物的合成与生物活性初步研究

发布时间：2018-03-08 09:38

  本文选题：炔基　切入点：铵基叶立德　出处：《华东师范大学》2017年硕士论文　论文类型：学位论文

【摘要】：炔基广泛存在于天然产物和一些药物中,尤其是抗癌药中,主要是由于炔基能和一些靶蛋白的半胱氨酸残基上的巯基会发生加成反应而形成共价作用,进而增强了药物与一些靶点蛋白的结合而更好地发挥药物作用。炔基是一个高能量、不饱和的活泼官能团,很容易与其他基团如氨基、羟基、亚胺、重氮等发生反应,所以在含有多官能团的复杂分子中快速引入炔基是不易的。基于亚胺捕捉铵基叶立德的多组分反应(MCRs),我们使用一些简单原料通过"一锅"法成功的构建含多官能团、结构多样性的炔酰胺取代的α,β-二氨基酸酯衍生物4,并研究了其生物活性,并初步对其进行构效关系研究。论文第一章,介绍了炔基在抗癌药物中的重要作用及其构建方法,并在课题组现有研究基础上提出了本论文的研究构思和课题目标。论文第二章,我们首先创建了一种以芳基重氮甲酸酯1、丙炔酰胺2和亚胺3为底物,醋酸铑为催化剂的"一锅"法以较好的收率和高非对映选择性成功地实现了构建炔酰胺取代的α,β-二氨基酸酯衍生物4。论文第三章,我们对这类新型α,β-二氨基酸酯衍生物4进行生物学抗肿瘤或抗癌活性研究,发现这类化合物在结肠癌和人肝癌细胞中初步显示了良好的生物学抗癌活性,IC50值在几微摩尔水平。而后,进行构效关系研究发现,不带羟基的炔酰胺取代的产物4抗癌活性可达到纳摩尔级别,尤其是在人骨肉瘤SJSA-1细胞中IC50值可达9.56 nM,表明羟基为非必须官能团;当炔基被烯基或烷基取代或关环所得苯并VA唑哌嗪酮类衍生物7,直接无抗癌作用,说明炔基是该类化合物表现抗癌作用的关键因素。总之,我们设计合成的炔酰胺取代的α,β-二氨基酸酯衍生物4是一类非常有效的潜在抗癌药物,这为我们后续的药理学研究提供了物质基础,为成药性研究提供了可能性。
[Abstract]:Alkynyl widely exists in some natural products and drugs, especially anticancer drugs, mainly because of alkynyl thiol and some target protein cysteine residues on the addition reaction and the formation of covalent interactions, thereby enhancing the combination of drugs and some target proteins and better use of drugs. Alkynyl is a high energy, unsaturated active functional groups, easily with other groups such as hydroxyl, amino, imino, diazotization reaction, so the complex molecules containing multiple functional groups in the rapid introduction of alkynyl is not easy. Multicomponent reaction of imines capture ammonium ylide (based on MCRs), we use some simple construction materials with multi functional success through a "one pot" method, structural diversity of alkyne substituted alpha, beta two amino acid ester derivative 4, and study its biological activity, and carries on the preliminary study on structure-activity relationship theory. The first chapter introduces the important role of alkyne in anti-cancer medicament and its construction method, and put forward the research ideas and research goals of this thesis in the research group. Based on the existing research in the second chapter, we first create a aryl diazonium acid ester amide 1, propargyl imine 3 and 2 as the substrate, rhodium acetate as catalyst of the "one pot" method with good yield and high diastereoselectivity were successfully constructed alkyne substituted alpha, beta two amino acid ester derivatives of 4. in the third chapter, we for this type of alpha, beta two amino acid ester derivatives in biological anti-tumor or 4 study on the anticancer activity of these compounds found in primary colon cancer and hepatocellular carcinoma showed good biological anticancer activity, IC50 value in a few Moore level. Then, structure-activity relationship study found that the product of alkyne without hydroxyl substituted 4 anticancer activity Can reach the level especially in the nanomolar, human osteosarcoma SJSA-1 cells in IC50 value can reach 9.56 nM, which indicated that hydroxyl for non essential functional groups; when alkynyl or alkenyl or alkyl substituted by the cyclization of benzo VA oxazole ketone piperazine derivative 7, no direct antitumor effect, that is the key factor of acetylenic compounds expression of anti-cancer effects. In short, we design the synthesis of alkyne substituted alpha, beta two amino acid ester derivative 4 is a kind of potential anticancer drugs are very effective, which provides the material basis for our further research into the pharmacology, drug research provides a possibility.

【学位授予单位】：华东师范大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914;R96
，

本文编号：1583375