4H-吡喃类及喹喔啉类化合物的合成及生物活性研究

发布时间：2018-03-12 19:01

本文选题：4H-吡喃　切入点：喹喔啉衍生物　出处：《辽宁大学》2017年硕士论文　论文类型：学位论文

【摘要】：含氧、氮芳杂环化合物被广泛应用于抗肿瘤、抗菌剂,抗病毒,消炎方面,已经成为当今新药研究的热门领域,其中4-芳基-4H-吡喃类及喹喔啉类有其各自特有的抗菌、抗肿瘤机制,天然产物中已发现的4-芳基-4H-吡喃类衍生物能够与肿瘤细胞的秋水仙素位点或邻近位点结合,从而抑制微管蛋白活性,导致肿瘤凋亡。本论文第一章运用骨架跃迁原理和局部修饰原理,以4-芳基-苯并吡喃母核为先导化合物,设计了4H-吡喃类化合物。本文以取代苯甲醛,和丙二腈经经克脑文格尔反应,合成芳基甲叉基丙二腈,再与β-酮基酯环合得到目标化合物。共合成25个4H吡喃类衍生物20a-20j以及21a-21o,结构经IR,1H-NMR的确认,部分化合物同时经过13C-NMR,MS结构确认。采用MTT法,测定了4H-吡喃类目标化合物20a、20b、20c、20d、20e、20f、20g、20h、21b、21c和21n对人肝癌细胞BL7402的抗肿瘤活性。其中9个化合物的活性优于阳性对照药5-Fu,尤其是目标产物20b、20g、21b在体外显示了很好的药理活性,它们对BL7402的IC50值分别为24.04μmol/L、38.20μmol/L、21.3μmol/L,分别是阳性对照药的5.75倍、1.61倍、6.47倍,初步分析了该类衍生物的构效关系。另外,论文以为5-氟-2硝基苯胺为起始原料,经芳环的亲核取代,得到5-L-脯氨醇-2硝基苯胺,再经Pd/C-甲酸铵还原,得到4-L-脯氨醇邻苯二胺,然后与α-氯-取代苯乙酮环合,得到喹喔啉母核,再与酸经缩合得到目标化合物。共8个化合物均经过红外光谱以及1H-NMR结构确认,并从中选取4个目标产物做抗菌活性测定。
[Abstract]:Aromatic heterocyclic compounds containing oxygen and nitrogen have been widely used in anti-tumor, antimicrobial, antiviral and anti-inflammatory fields, and have become a hot field in the research of new drugs. Among them, 4-aryl-4H-pyrans and quinoxaline have their own unique antibacterial properties. Antitumor mechanism, 4-aryl-4H-pyran derivatives found in natural products can bind to colchicine sites or adjacent sites of tumor cells, thereby inhibiting tubulin activity. In chapter 1, we use the skeleton transition principle and the local modification principle to design 4H-pyran compounds with 4-aryl-benzopyran parent nucleus as the lead compounds. Aryl methyl malonitrile was synthesized from malonitrile by Knovinger reaction, and then cyclized with 尾 -keto ester to obtain the target compound. A total of 25 4H pyran derivatives 20a-20j and 21a-21owere synthesized. The structures were confirmed by IR ~ 1H-NMR. Some of the compounds were confirmed by 13C-NMRMS at the same time. MTT method was used. The antitumor activities of 4H-pyran target compounds 20aHX 20bn20cn20dCn20eO20fFN 20fU 20htbc21c and 21n on human hepatoma cell line BL7402 were determined. The activities of 9 of them were superior to those of positive control drug 5-Fu.In particular, the target product 20bn20g21b showed a good pharmacological activity in vitro, and the antitumor activity of 4H-pyran group was better than that of 5-Fu.In particular, the target product, 20bng21b, showed a good pharmacological activity in vitro. Their IC50 values to BL7402 were 24.04 渭 mol / L ~ 38.20 渭 mol / L ~ 21.3 渭 mol 路L ~ (-1), respectively, which were 5.75 times, 1.61 times and 6.47 times of that of a positive control drug, respectively. The structure-activity relationship of these derivatives was preliminarily analyzed. 5-L-proline 2-nitroaniline was synthesized, then reduced by PD / C- ammonium formate to obtain 4-L-proline o-phenylenediamine, then cyclized with 伪 -chloro-substituted acetophenone to obtain quinoxaline mother nucleus. The eight compounds were confirmed by IR and 1H-NMR, and four of them were selected for the determination of antimicrobial activity.
【学位授予单位】：辽宁大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914;R96

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