双环吡啶与多环喹啉类化合物的合成及抗肿瘤活性研究

【作者】 陈亮；

【导师】 林军； 严胜骄；

【作者基本信息】 云南大学 ， 制药工程， 2017， 硕士

【摘要】 含氮杂环化合物广泛存在于各种天然产物之中,由于其多样的结构以及独特的生理活性,在药物设计和合成之中有着重要的地位。其中的双环吡啶类以及喹啉类则由于其丰富的生理活性而在医药领域被广泛的运用。而有机氟化合物由于氟原子特殊的性质,使得含氟化合物的生理活性得以加强。本文分别设计合成了含氟双环吡啶季铵盐类以及多环喹啉类化合物,合成过程绿色、高效和环保,反应条件温和,产率较高,后处理简单。第一章:介绍了双环吡啶和喹啉类化合物在药物中的运用,含氟有机化合物的活性以及多功能合成子杂环烯酮缩胺的结构和反应特点。第二章:利用色酮-3-甲醛Ⅱ-1与N-节基硝基烯酮缩胺Ⅱ-2在乙醇中反应,一锅法合成了双环吡啶季铵盐类及其中间体化合物。目标产物通过直接抽滤便得到,无需额外的后处理操作。该方法具有合成成本低,反应溶剂环保,反应条件温和,原子经济性,高产率及产物具有潜在的生物活性等显著优势。R = Cl,F,H,CH3;Ar= 4-N02Ph,4-CF3Ph,4-CNPh,4-FPh,4-CIPh,Ph,4-MePh,4-MeOPh,3-FPh etc.第三章:利用2-氟苯甲醛类Ⅲ-1与HKAs Ⅲ-2反应,1,4-dioxane作为溶剂,piperidine和CaC12作为催化剂条件下加热反应得到了多环喹啉类化合物Ⅲ-3和Ⅲ-4。反应产率高、绿色以及条件温和,无需柱层析后处理。并对所得化合物进行了体外肿瘤细胞株的活性测试,部分化合物显示出了较好的抗肿瘤活性。通过1HNMR,13CNMR,IR和HRMS等谱学手段对以上两大类共114个化合物进行了结构确证。每类化合物中选取了一个化合物进行X-Ray单晶检测。更多还原

【Abstract】 Nitrogen-containing heterocyclic compounds are widely present in a variety of natural products,because of its diverse structure and unique biological activity,it has an important position in the design and synthesis of drugs.The bicyclic pyridines and quinolines derivatives are widely used in the pharmaceutical field due to their rich biological activity.Due to the special property of fluorine atoms,the organic fluorine compounds enhance the biological activity.In this paper,fluorine-containing bicyclic pyridinium derivatives and polycyclic quinoline derivatives were designed and synthesized.The synthesis process was green,high efficiency and environmental protection.The reaction conditions were mild,highly yield and the simple post-treatment.The first chapter:We describe the use of bicyclic pyridine and quinoline compounds in drugs,the activity of fluorine-containing organic compounds,and the structure and reaction characteristics of the heterocyclic ketene amines as a type of versatile synthetic intermediate.In the second chapter:A concise and eco-friendly route for the synthesis of highly functionalized bicyclic pyridinium derivatives via one-step reaction of the chromone-3-carboxaldehyde(Ⅱ-1)and N-benzyl nitro ketene aminals(Ⅱ-2)in ethanol media has been developed.The targeted compound can efficiently obtain by filter without extra post-treatment.The reaction is particularly attractive due to following features:low-cost and biocompatibility solvent,mild temperature,atom economy,high yields,and potential biological activity product.R = CI,F,H,CH3;Ar=4-NO2Ph,4-CF3Ph,4-CNPh,4-FPh,4-CIPh,Ph,4-MePh,4-MeOPh,3-FPh etc.The third chapter:The polycyclic quinolines Ⅲ-3 and Ⅲ-4 were synthesized by the reaction of 2-fluorobenzaldehyde Ⅲ-1 with HKAs Ⅲ-2 in solvent of 1,4-dioxane while piperidine and CaCl2 as catalyst.The reaction has highly yield,green and mildlyAll the structures of 114 synthetic compounds were confirmed by 1H NMR,13C NMR,and HRMS spectra.One compound that selected from each category was confirmed through the X-Ray analysis.conditions,without column chromatography.Then the obtained compounds were tested for the activity of in vitro tumor cell lines,and some of the compounds were showed good antitumor activity.更多还原