【作者】 戚映丹；

【导师】 杨根生；

【作者基本信息】 浙江工业大学 ， 药物化学， 2009， 硕士

【摘要】 布洛芬(Ibuprofen)为非甾体类解热镇痛药,其消炎、镇痛、解热作用显著,不良反应较小,在世界范围内得到广泛应用,目前已成为全球最畅销的非处方药之一。S-布洛芬的药理活性为R-布洛芬的100倍,且R-布洛芬可能有些毒副作用,故消旋布洛芬的立体拆分是目前研究的一个热点。目前,文献报道的生物法拆分2-芳基丙酸类药物的途径主要有用酶或微生物进行立体选择性水解(酯、酰胺和腈)、酯化等。磷酸酯是公认的各种酶包括许多蛋白酶和酯酶的有效过渡态类似物抑制剂。其中,1-芳基磷酸酯乙烷是具潜在生物活性的化合物,主要作为非甾体消炎镇痛药2-芳基丙酸类的类似物,如布洛芬。现已经证实1-芳基磷酸酯乙烷经过动物免疫得到的抗体具备催化立体选择性水解的功能。本论文中,描述了一类新的生物催化剂,既抗体酶也叫催化抗体,是具有催化活性的免疫球蛋白。此类催化抗体能有效的水解外消旋布洛芬甲酯分离得到S-布洛芬。我们以抗体酶的设计策略中的过渡态理论为基础,模拟酯水解的四面体中间过渡态结构,以磷原子为四面体过渡态类似物的中心原子来设计和合成了不同的半抗原和全抗原。用目标抗原作为免疫原,经小鼠免疫单克隆抗体,然后测定抗体在水介质中与反胶束体系中的催化布洛芬甲酯选择性水解的活性。更多还原

【Abstract】 Ibuprofen, (R,S)-2-(4-isobutylphenyl) propionic acid, is a widely used nonsteroidal anti-inflammatory drug which belongs to the family of 2-arylpropionic acid derivatives. The pharmaceutical activity of 2-arylpropionic acid derivatives is often dramatically dependent on the chirality of these compounds. In the case of ibuprofen, because of the asymmetric carbon in the second position, the S-(+)-enantiomer is known to be about 100 times more active than its R-(-)-enantiomer. Chemical synthesis of the S-isomer involving diastereomeric crystallization from a racemic acid mixture has been reported. Considerable efforts have been made in improving the methods of its asymmetric synthesis. A resolution of racemic ibuprofen has been achieved by enzyme-catalyzed or microbe cells enantioselective hydrolysis of the corresponding racemic esters, amides and nitriles.Phosphonates are recognized as effective transition-state analogue inhibitors for a variety of enzymes including a number of proteases and esterase. Therein, 1-arylethylphosphonates are of interest as potential biologically active compounds, primarily as phosphorus analogs of 2-arylpropionic acids that are known as nonsteroid antiphlogistic and analgetic drugs, such as ibuprofen. It was demonstrated that 1-arylethylphosphonates caused formation in animal organism of antibodies possessing properties of catalysts of stereospecific hydrolysis.In this paper, we describe a new biocatalyst, catalytic antibodies, that produced ibuprofen from their corresponding racemic ester in enantiomerically pure (S)-configuration. The biocatalyzed hydrolysis reaction can be carried out with antibodies to achieve high enantioselectivity. To elicit catalytic antibodies for the ibuprofen methyl ester hydrolysis, the tetrahedron structure compound contained phosphorus was designed and synthesized as hapten which is mimic of TSA, based on the transition state theory. The hapten was covalently attached to bovine serum albumin (BSA) to be used as immunogens. Catalytic antibodies were prepared from mice and sequential purification by ammonium sulfate precipitation and affinity chromatography.Then, Kinetic analysis of the catalytic antibody-catalyzed reaction was found to be possible in a reverse micelle reaction system based on sodium bis (2-ethylhexyl) sodium sulfosuccinate (AOT) in isooctane. Kinetic studies showed that hydrolysis in the microemulsion system follows Michaelis-Menten kinetics.更多还原