白杨素氨基酸类化合物的合成、表征及抗癌活性研究

发布时间：2018-07-11 13:09

本文选题：白杨素 + 衍生物　；参考：《南华大学》2014年硕士论文

【摘要】：目的以白杨素为先导化合物，，设计、合成白杨素氨基酸类化合物，并初步探讨其抗癌活性及作用机制，以期获得高效、低毒、选择性好的抗癌先导化合物，为探索和开发新的抗癌药物提供理论依据。方法通过卤代、水解、缩合等化学反应对白杨素进行结构改造；采用四甲基偶氮唑蓝(MTT)法评价合成的白杨素衍生物对人胃癌细胞MGC-803和人肝癌细胞HepG2的增殖抑制作用；根据初步的细胞增殖实验结果，采用流式细胞术(flowcytometry，FCM)检测部分活性较好的衍生物对人胃癌细胞MGC-803的凋亡效应；通过Western blot探讨可能的分子机制。结果本文合成了不同系列的28个白杨素衍生物，其中22个化合物未见文献报道。所有目标化合物及相关中间体通过熔点(M.P.)、核磁共振(NMR)以及高分辨率质谱(ESI-TOF-MS)等手段进行结构确证。化合物的细胞增殖实验结果表明，与阳性药物顺铂（cisplatin，DDP）及母体化合物白杨素相比，多数合成的白杨素衍生物对MGC-803、HepG2细胞的增殖具有良好的抑制作用，其中化合物N-[4-(5-羟基-2-苯基-4H-苯并吡喃酮-7-氧基)丁酰基]异亮氨酸甲酯(20)对MGC-803细胞表现出比阳性对照更好的抑制作用。FCM和Western blot实验结果显示，化合物20能诱导MGC-803细胞凋亡、下调细胞中Bcl-xl蛋白表达以及上调Bax蛋白表达，且呈剂量依赖性。结论本课题设计合成了不同系列结构新型的白杨素衍生物，拓展了白杨素衍生物的研究范畴；初步完成了所合成的白杨素衍生物的细胞增殖抑制作用的评价，并探讨其发挥抗癌作用的可能机制，为进一步设计开发具有诱导肿瘤细胞凋亡效应的新药提供思路。
[Abstract]:Objective to design and synthesize the amino acid compounds of aspen with poplar as a leading compound, and to explore its anticancer activity and mechanism so as to obtain high efficiency, low toxicity and good selectivity. To provide theoretical basis for exploring and developing new anticancer drugs. Methods by halogenation, hydrolysis, condensation and other chemical reactions, the structural modification of alginine was carried out, and the inhibitory effects of the synthesized derivatives on the proliferation of human gastric cancer cell line MGC-803 and human hepatocellular carcinoma cell line HepG2 were evaluated by MTT assay. According to the preliminary results of cell proliferation, flow cytometry (FCM) was used to detect the apoptotic effect of some active derivatives on human gastric cancer cell line MGC-803, and the possible molecular mechanism was explored by Western blot. Results 28 different series of white poplar derivatives were synthesized in this paper, 22 of which were not reported in literature. The structures of all the target compounds and their related intermediates were confirmed by means of melting point (M. P.), NMR and high resolution mass spectrometry (ESI-TOF-MS). The results of cell proliferation assay showed that compared with cisplatin (cisplatin DDP) and its parent compound, most of the synthesized derivatives had a good inhibitory effect on the proliferation of MGC-803 HepG2 cells. Among them, compound N- [4- (5-hydroxy-2-phenyl-4H-benzopyranone -7oxy) butyryl] methyl ester (20) showed a better inhibitory effect on MGC-803 cells than the positive control. FCM and Western blot experiments showed that compound 20 could induce apoptosis of MGC-803 cells. The expression of Bcl-xl protein and the expression of Bax protein were down-regulated in a dose-dependent manner. Conclusion in this paper, we have designed and synthesized new series of white salicyrin derivatives with different structures, expanded the scope of research on them, and preliminarily completed the evaluation of the inhibitory effect of the synthesized derivatives on cell proliferation. The possible mechanism of its anticancer effect was also discussed, which provided ideas for the further design and development of new drugs with the effect of inducing apoptosis of tumor cells.
【学位授予单位】：南华大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914;R96

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