新型PPARs多靶点激动剂的设计与合成

发布时间：2018-07-10 03:09

本文选题：PPARs + 多靶点激动剂　；参考：《天津医科大学》2015年硕士论文

【摘要】：目的:过氧化物酶体增殖因子活化受体(peroxisome proliferators activated receptor,PPAR)是核受体家族成员之一,包括α、γ、δ三个亚型,与糖尿病、肥胖症、脂质异常等疾病的发生发展密切相关。噻唑烷二酮类PPARγ激动剂作为抗糖尿病药物由于存在心脏安全性等副作用,已在临床限制使用。选择性的激动PPARγ亚型是产生这些副作用的主要原因。近年来,随着糖尿病形成机理研究的不断深入,多靶点协同作用的PPARα/γ双重激动剂、PPARα/γ/δ共激动剂等已引起人们的广泛关注。本论文利用计算机辅助设计先进手段,设计并合成具有降糖、降脂协同作用的PPARs多靶点激动剂,以期避免现有噻唑烷二酮类药物的副作用,为新型多靶点抗糖尿病药物研发奠定基础。方法:(1)以罗格列酮为先导物,采用骨架跃迁的策略对其极性头部、中间链状结构和疏水尾部进行结构改造,建立了类似物分子库。然后通过分子对接评价这些类似物与PPARα/γ/δ的结合情况,并且预测其ADMET性质,筛选出8个具有较好结合构像和药动学性质的PPARα/γ/δ共激动剂。以原始配体为对照,对其中的代表化合物1进行分子动力学模拟研究,结果表明化合物1能与靶点更稳定的结合,从而为新型PPARs多靶点激动剂类降糖药的研发提供了结构参考。(2)借鉴苯氧基烷酸类PPARa激动剂和噻唑烷二酮类PPARγ激动剂的共同结构特征,根据药物化学的拼合原理,将苯氧基烷酸类药物的极性头部和噻唑烷二酮类药物的疏水尾部整合在一个分子中,设计了具有协同增效作用的PPARα/γ/δ共激动剂,以期避免现有噻唑烷二酮类药物的副作用。(3)以对苯二酚为原料,与2-溴-2-甲基丙二酸乙酯反应,生成单取代的中间体2-(4-羟基-苯氧基)-2-甲基-丙酸乙酯(WB-1-2)。该中间体进一步与各种卤化物反应,如苯丙基氯,2-氯苯乙酮,3-氯甲基吡啶盐酸盐,5-乙基-2氯乙基吡啶,N-氯乙基咔唑,N-氯丙基咔唑,N-氯乙基吲哚,N-氯乙基苯并咪唑,N-氯丙基苯并咪唑,生成各种酯类化合物,然后水解得到羧酸类目标化合物。目标化合物通过氢谱、碳谱及质谱确认结构。结果:(1)本论文对罗格列酮进行结构改造,筛选出8个具有较好结合构像和药动学性质的PPARα/γ/δ共激动剂。对其中的代表化合物1进行了分子动力学模拟研究,结果表明化合物1能与靶点更稳定的结合。(2)本论文将苯氧基烷酸类药物的极性头部和噻唑烷二酮类药物的疏水尾部整合在一个分子中,设计了具有协同增效作用的PPARα/γ/δ共激动剂。对其中部分化合物进行了化学合成,得到了18个目标化合物并确证其结构。结论:本论文以PPARα/γ/δ为药物作用靶标,设计了具有多靶点作用的PPARα/γ/δ激动剂。对代表性化合物进行合成,得到18个目标化合物,其化学结构经过氢谱、碳谱和质谱确证。本论文的工作为发现具有深入研究价值的降糖药物先导物奠定了基础。
[Abstract]:Objective: peroxisome proliferator factor-activated receptor (peroxisome proliferators activated) is a member of nuclear receptor family, including 伪, 纬, 未 subtypes, which is closely related to the occurrence and development of diabetes, obesity, lipid abnormalities and other diseases. Thiazolidinedione PPAR 纬 agonists have been restricted in clinical use as antidiabetic drugs due to cardiac safety and other side effects. Selective activation of PPAR 纬 subtypes is the main cause of these side effects. In recent years, with the development of the mechanism of diabetes mellitus, the multi-target synergistic PPAR 伪 / 纬 dual agonist, PPAR 伪 / 纬 / 未 co-agonist, has attracted much attention. In this paper, we designed and synthesized PPARs multi-target agonists with the synergistic effect of hypoglycemic and lipid-lowering by computer aided design, in order to avoid the side effects of the existing thiazolidinedione drugs. To lay a foundation for the research and development of new multi-target anti-diabetic drugs. Methods: (1) with rosiglitazone as the leader, the structure of polar head, intermediate chain structure and hydrophobic tail were modified by the strategy of skeleton transition, and the analogous molecular library was established. Then the binding of these analogues to PPAR 伪 / 纬 / 未 was evaluated by molecular docking, and ADMET properties were predicted. Eight PPAR 伪 / 纬 / 未 co-agonists with good conformation and pharmacokinetic properties were selected. The molecular dynamics simulation of the representative compound 1 was carried out by using the original ligand as a control. The results showed that compound 1 could bind to the target more stably. It provides a structural reference for the research and development of novel PPARs multitarget agonists. (2) based on the common structural characteristics of phenoxyalkanoic acid PPARa agonists and thiazolidinedione PPAR 纬 agonists, according to the principle of pharmacochemistry, The polar head of phenoxy alkanoic acid and the hydrophobic tail of thiazolidinedione were integrated into one molecule, and a synergistic PPAR 伪 / 纬 / 未 co-agonist was designed. In order to avoid the side effects of the existing thiazolidinediketones. (3) the monosubstituted intermediate 2- (4-hydroxy-phenoxy) -2-methyl-propionate (WB-1-2) was synthesized by the reaction of hydroquinone with ethyl 2-bromo-2-methylmalonate. The intermediate further reacts with various halides, For example, phenylpropyl chloro 2-chloro-acetophenone 3-chloromethylpyridine hydrochloride, 5-ethyl 2-chloroethyl pyridine, N-chloropropyl carbazole, N-chloropropyl indole-N-chloroethyl benzimidazole, N-chloropropyl benzimidazole, The carboxylic acid target compounds are then hydrolyzed. The target compounds were identified by hydrogen, carbon and mass spectra. Results: (1) eight PPAR 伪 / 纬 / 未 co-agonists with good conformational and pharmacokinetic properties were screened by structural modification of rosiglitazone. Molecular dynamics simulation of one of the representative compounds 1 was carried out. The results showed that compound 1 could bind to the target more stably. (2) in this paper, the polar head of phenoxy alkanoic acid and the hydrophobic tail of thiazolidinedione were integrated into one molecule, and a synergistic PPAR 伪 / 纬 / 未 co-agonist was designed. Some of the compounds were chemically synthesized and 18 target compounds were obtained and their structures were confirmed. Conclusion: in this thesis, PPAR 伪 / 纬 / 未 agonists with multiple targets were designed. Eighteen target compounds were synthesized and their chemical structures were confirmed by hydrogen spectrum, carbon spectrum and mass spectrometry. The work of this paper lays a foundation for the discovery of hypoglycemic drug precursors.
【学位授予单位】：天津医科大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R91;R914.5

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