【作者】 张欣；

【导师】 闫红；

【作者基本信息】 北京工业大学 ， 生物化学与分子生物学， 2012， 硕士

【摘要】 11β-羟类固醇脱氢酶Ⅰ型(11beta-hydroxysteroid dehydrogenase,11β-HSD1)作为Ⅱ型糖尿病治疗药物的新靶点已经受到越来越多的关注。11β-HSD1抑制剂的发现以及相关药物的研究，有望改变传统Ⅱ型糖尿病药物存在的低血糖，体重下降和心血管影响等副作用，成为一种对胰岛β细胞具有保护作用的抗糖尿病药物。本文通过对已知11β-HSD1抑制剂的构效关系进行研究，设计了一类新型的11β-HSD1抑制剂-----1,4-二芳基-1,4-二氢吡嗪类化合物，对其活性虚拟筛选和合成方法的研究，可为11β-HSD1抑制剂的研发提供理论和实验基础。本论文在对已知的11β-HSD1抑制剂与11β-HSD1结合模式的研究，确定了其作用模式主要为范德华力，疏水作用力，氢键和较高的空间契合度。在其构效关系研究的基础上，设计出了一系列的1,4-二芳基-1,4-二氢吡嗪类化合物。利用计算机辅助药物设计的方法，在AutoDock4.0平台上，对所设计的化合物进行虚拟筛选。通过对其结合模式与活性之间关系的讨论，确定要合成的1,4-二芳基-1,4-二氢吡嗪的分子结构。通过对1,4-二氢吡嗪合成方法的综述，确定1,4-二芳基-1,4-二氢吡嗪的合成路线，即以重氮乙酰乙酸乙酯和芳胺为原料，以醋酸铑为催化剂，合成N,N-二烷基芳胺中间体，再与芳胺反应关环。通过对合成过程中的影响因素(催化剂种类和反应物料比等)进行研究，确定该方法的最佳反应条件。对合成过程中的副产物N-芳基乙酰乙酯的生成机制进行研究，并讨论了氧气和醋酸铑对其生成的影响。通过核磁共振氢谱和碳谱等，对目标化合物的结构进行分析确认。更多还原

【Abstract】 11Beta-hydroxysteroid dehydrogenase type Ⅰ (11β-HSD1) as a new thera-peutic target of Type Ⅱ Diabetes has attracted more and more attention. The re-search on11β-HSD1inhibitor can reduce the side effects of the traditional drugs ofType Ⅱ Diabetes, such as hypoglycemia, weight loss and cardiovascular risks, andprovide a protective on β-cells in the pancreas. A series of1,4-diaryl-1,4-dihydropyrazines have been designed based on the study of struc-ture-activity relationship of the11β-HSD1inhibitors. These inhibitory activities werevirtual screened and synthetic routes were investigated in order to provide theoreticaland experimental basis for the development of new11β-HSD1inhibitors.Bases on the study of binding mode of11β-HSD1and its inhibitors, hydrophobic,van der waals’, hydrogen-bond interaction and space fit were found as the interactivemodels. Then a series of1,4-diaryl-1,4-dihydropyrazines as inhibitors of11β-HSD1have been designed. These inhibitory activities were virtual screened by docking al-gorithm of Computer-Aided Drug Design (CADD) on the platform of AutoDock4.0.The relationships between binding mode and inhibitory activity of these compoundshad been studied to confirm the structures of the target compounds.Based on the review of the preparations of1,4-dihydropyrazines, the syntheticroute for the1,4-diaryl-1,4-dihydropyrazines were designed. These were synthesizedby the cyclization reactions of N,N-dialkyl-anilines with anilines, the intermediateN,N-dialkyl-anilines were alkylated on anilines by ethyl2-diazo acetoacetate with therhodium acetate dimer as the catalyst. The appropriate conditions were optimizated onthe influence factors of catalysts and molar ratio of reactants. On the prepareation ofN,N-dialkyl-anilines, the N-aryloxamates was found as the main by-product and oxi-dized by the moleculars oxygen with rhodium acetate dimeras catalyst. The structuresof synthesized compounds are identified by1H NMR and13C NMR.更多还原