四氢-β-咔啉类与双吲哚类化合物合成及抗肿瘤活性研究

发布时间：2018-04-06 07:40

本文选题：四氢-β-咔啉类　切入点：Pictet-Spengler反应　出处：《天津科技大学》2014年硕士论文

【摘要】：四氢-β-咔啉类化合物是属于分布于自然界的吲哚生物碱,具有抗肿瘤、抗菌、抗高血压及治疗阿尔兹海默症等多种生物活性,近年来,四氢-p-咔啉类化合物以其独特的性质和结构,引起越来越多的人关注。双吲哚类衍生物作为杂环化合物一种重要的类别所为人知晓,并且是研发和制药工业中具有生物活性的中间产品,不仅可以增加人体内荷尔蒙的自然代谢,而且在预防癌症方面也是有效的。Pictet-Spengler缩合反应是在1911年被AmePictet和TheodorSpengler发现的,现已经成为了在合成p-咔啉类化合物方面中至关重要的方法,除此之外,它也应用于更多的复杂结构吲哚生物碱的合成。论文运用Pictet-Spengler反应方法,合成四氢-p-咔啉类化合物。首先以吲哚和5-溴吲哚为原料,经过亲核加成、环合、还原、Pictet-Spengler反应等5-6步反应,合成了8个四氢-p-咔啉类衍生物,通过对不同反应试剂、反应时间和反应温度的优化,反应的总产率均达到20%-25%。利用核磁共振氢谱、碳谱等方法对目标化合物的结构进行表征。课题以吲哚为原料,经过付克酰基化、黄鸣龙反应、还原、Pictet-Spengler反应等4-5步反应,合成了6个双吲哚结构化合物,通过对不同反应试剂、反应时间和反应温度的优化,反应的总产率均达到27%～37%。利用核磁共振氢谱、碳谱,质谱及二维核磁谱图等方法对目标化合物的结构进行表征。综上所述,合成14个目标化合物和4个中间产物,其中11个化合物未见报道。在此基础上,对双吲哚类化合物进行了体外肿瘤细胞抑制活性的测试,所选用的三种癌细胞为人白血病细胞(K562)、人肝癌细胞(HepG2)和人结肠癌细胞(HT-29)。活性测试结果为：2,2'-二(3,3'-N-苄基-3-1H-吲哚基丙酰胺)苯基甲烷(化合物13),2,2'-二(3,3'-N-苄基-3-1H-吲哚基丙酰胺)对硝基苯基甲烷(化合物16),2,2'-二(3,3'-N-苄基-3-1H-吲哚基丙酰胺)对氟苯基甲烷(化合物17),2,2'-二(3,3'-N-苄基-3-1H-吲哚基丙酰胺)间甲氧基苯基甲烷(化合物18)对人白血病细胞(K562)肿瘤细胞有着一定的生长抑制作用,其IC50值分别为56.19μM,90.71μM,58.55μM,67.22μM,对人肝癌细胞(HepG2)和人结肠癌细胞(HT-29)均无抑制作用。测试结果表明：与吲哚类似物反应的苯甲醛,苯环对位连有弱吸电基与间位连有供电基的分子,其抗肿瘤活性较好。
[Abstract]:Tetrahydro- 尾 -carboline is an indole alkaloid distributed in nature. It has many biological activities such as anti-tumor, antibacterial, anti-hypertension and treating Alzheimer's disease.Tetrahydrogen-p-carboline compounds have attracted more and more attention due to their unique properties and structures.Bisindole derivatives are known as an important class of heterocyclic compounds and are bioactive intermediates in the R & D and pharmaceutical industries, which not only increase the natural metabolism of hormones in humans,And also effective in preventing cancer. Pictet-Spengler condensation was discovered by AmePictet and TheodorSpengler in 1911 and has become a crucial method in the synthesis of p-carboline compounds.It is also used in the synthesis of more complex indole alkaloids.In this paper, tetrahydrogen-p-carboline compounds were synthesized by Pictet-Spengler reaction.Firstly, eight tetrahydro-p-carboline derivatives were synthesized from indole and 5-bromoindole by 5-6 steps of nucleophilic addition, cyclization and reduction Pictet-Spengler reaction.The total yield of the reaction was 20-25.The structure of the target compounds was characterized by nuclear magnetic resonance spectroscopy and carbon spectroscopy.In this paper, six diindole compounds were synthesized from indole by 4-5 steps of Fu acylation, Huang Minglong reaction, reduction Pictet-Spengler reaction and so on. Different reaction reagents, reaction time and reaction temperature were optimized.The total yield of the reaction was 27% and 37% respectively.The structure of the target compound was characterized by nuclear magnetic resonance spectroscopy, carbon spectrum, mass spectrometry and two-dimensional NMR spectroscopy.In conclusion, 14 target compounds and 4 intermediates were synthesized, of which 11 compounds were not reported.On this basis, the inhibitory activity of diindole compounds on tumor cells was tested in vitro. Three kinds of cancer cells were selected as human leukemic cells, human hepatocellular carcinoma cell line (HepG2) and human colon cancer cell line (HT-29C).Their IC50 values were 56.19 渭 m ~ (90.71 渭 m) and 58.55 渭 M ~ (67.22 渭 M), respectively, which had no inhibitory effect on human hepatoma cell line HepG2) and human colon cancer cell line (HT-29).The results showed that the benzaldehyde, benzaldehyde ring with weak electricity-absorbing group and mesopotopic power supply group reacted with indole-analogue, and the anti-tumor activity of benzaldehyde was better than that of other molecules.
【学位授予单位】：天津科技大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5;R96

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