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摘要HMG-CoA还原酶抑制剂的结构是其亲水部分，亲脂部分通过键桥嫁接在一起的。对于大部分HMG-CoA还原酶抑制剂而言，为了增加其药物活性，降低其生理毒性，他汀类药物的结构改进主要集中在对其亲脂母环和连接部分上，而对于亲水侧链的结构改进却很少有报道。研究发现，一些药物在特殊位置引入二氟亚甲基后其生物活性得到了显著改善，因而本文拟在HMG-CoA还原酶抑制剂亲水侧链的4号位引入二氟亚甲基以期得到药效更好和毒副作用更小的新型HMG-CoA还原酶抑制剂。本文的研究内容主要分为以下三个部分：
- 上一篇：Piancatelli重排反应在药物中间体合成中的应用
- 下一篇：局部封闭敷贴法TA的皮肤致敏试验研究
1.首先，使用三种他汀母核丙烯醛与溴二氟乙酸乙酯的Reformatsky反应合成得到β-羟基酯，再通过Claisen缩合得到叔丁酯，接着经过硼氢化钠还原得到双羟基叔丁酯，最后将得到的双羟基叔丁酯经氢氧化钠碱性水解再经稀盐酸酸化处理最终合成了偕二氟取代的他汀类似物。31988
2.其次，对合成的偕二氟取代的他汀类似物进行生物活性测试。结果显示，其生物活性优于市售他汀类药物。于是，我们又设计了系列化合物，即对他汀亲水侧链作一些氟代修饰的他汀化合物并通过类似链增长的方法合成并作了生物活性测试。毕业论文
3.对已合成和即将合成的系列氟代HMG-CoA还原酶抑制剂通过分子对接以预测配体与配体结合方式并找到与关键残基相互作用的基团。通过对氟代他汀活性-结构关系的研究,探讨氟原子的引入对他汀类化合物活性影响的一般规律。
Design, synthesis and docking study of fluorine substituted HMG-CoA reductase inhibitors
Abstract: HMG-CoA reductase share rigid, hydrophobic groups that are covalently linked to the hydrophilic moiety. For most HMG-CoA reductase inhibitors, to improve their biological activity and reduce their side effects, the structure modifications are mainly focused on their lipophilic portion. While the modifications on the hydroxyl-valerolactone side chains have seldom reported.It has been revealed that many compounds with the gem-difluoromethylene group in the specific position shows significant improvement in their biological activities.Therefore,we performed the introduction of gem-difluoromethylene group of HMG-CoA reductase inhibitors in order to get the novel HMG-CoA reductase inhibitors with high biological and low side effects. The dissertation is pided into the following three parts:
1. Styryl α,α-difluoromethyl β-hydroxy esters were obtained by using zinc-mediated Reformatsky reaction of cinnamyl aldehyde derivatives 2 with bromodifluoroacetate. Claisen condensation of 3 produced δ-hydroxy-β-keto esters 4, which were reduced by NaBH4 to provide β,δ-diols 5. Acetonide formation of diols 5 afforded the desired and important intermediates 6. With gem-difluoromethylenated acetonides 6 in hand, we then test the chemistry to convert 6 into the desired styryl γ,γ-difluoromethyl β-hydroxy δ-lactones 8. Then, we studied the grafting of lipophilic mother nucleus and hydrophilic side chains grafted, but it was not succeeded. Finally, on the basis of synthesis cinnamic aldehyde substrate, gem-difluroromenthylene statin analogues were synthesized ultimately from the three kinds of statins parent nucleus of acrolein.
2. We tested the pharmaceutical activities on the synthesized gem-difluroromenthylene statin analogues.As a result,it shows better effect than the statins medicine sold in the market.In order to find out the influence to hydrophilic part of statins , we have designed another series of compounds ,which make some fluoro modification hydrophilic part of statins.Then we synthesized them through the similar method and tested their pharmaceutical activities.
3. Molecular docking studies were performed on the synthesized and to be synthesized fluorine substituted HMG-CoA reductase inhibitors to predict the binding mode of the ligand and receptor,which we can find some groups interacted with these key residues.Through analyzing the link between structure and activity level, we would like to draw some conclusion about how the introduction of fluorine in different sites affect statins activity level.
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