Jaspine B类似物和阳离子抗菌肽模拟物的合成及生物活性评价

发布时间：2018-03-04 16:43

本文选题：Jaspine　切入点：B　出处：《郑州大学》2017年硕士论文　论文类型：学位论文

【摘要】：1.Jaspine B是从海洋生物海绵中提取出来的具有显著抗肿瘤活性的天然产物,其能够在0.01μg/mL的浓度下即可对多种肿瘤细胞有明显的抑制作用。我们以jaspine B的结构为模型,设计合成了14个jaspine B氮代类似物,通过MTT法测试其细胞毒活性,化合物2-3f和2-3g分别对前列腺癌细胞PC-3和乳腺癌细胞MCF-7的活性较好,IC50值分别为0.859μM和0.719μM。初步探究化合物2-3f对前列腺癌细胞PC-3的作用机制,流式细胞术检测细胞凋亡实验结果说明化合物2-3f不能诱导肿瘤细胞发生早期凋亡;蛋白质免疫印记实验结果表明化合物2-3f能够引起自噬标记蛋白表达量的变化;线粒体膜电位实验结果说明化合物2-3f能够诱导线粒体膜电位下降;LC3蛋白荧光共聚焦实验也说明化合物2-3f能够使自噬标记蛋白LC3表达量增加。以上结果说明化合物2-3f对肿瘤细胞作用机制是诱导肿瘤细胞发生自噬。2.抗菌肽是一种高效的抗菌谱广的且不易产生耐药性的新型抗菌化合物,设计合成小分子阳离子抗菌肽模拟物目的是为了开发新型抗菌候选药物。在实验室前期工作的基础上,我们将三氮唑环引入抗菌肽模拟物中合成26个小分子阳离子抗菌肽模拟物,测试这些化合物对四种敏感菌株的最低抑菌浓度,结果发现化合物3-5g,3-5h,3-5i,3-5y和3-5z的抗菌活性较好,继续测试这5个化合物对4种不同类型耐药菌株(产KPC的肺炎克雷伯菌,产NDM-1的大肠杆菌,MRSA耐甲氧西林的金黄色葡萄球菌和VRE耐万古霉素的肠球菌)的最低抑菌浓度,结果显示这5个化合物对耐药菌的抑菌活性均较好。红细胞溶血实验结果显示化合物3-5z具有较小的红细胞溶血毒性;血浆稳定性实验表明化合物3-5z在血浆中具有良好的稳定性,不易被血浆中的酶分解,经血浆处理6小时后其最低杀菌浓度仅增加一倍。
[Abstract]:1. Jaspine B is a natural product with remarkable antitumor activity extracted from marine sponge. It can inhibit many kinds of tumor cells at a concentration of 0.01 渭 g / mL. We use the structure of jaspine B as a model. Fourteen nitrogen analogues of jaspine B were designed and synthesized, and their cytotoxic activity was tested by MTT assay. The activity of compound 2-3f and 2-3g on prostate cancer cell PC-3 and breast cancer cell MCF-7 were 0.859 渭 M and 0.719 渭 M. respectively. The results of flow cytometry showed that compound 2-3f could not induce early apoptosis of tumor cells, and protein imprinting showed that compound 2-3f could induce the expression of autophagy marker protein. The results of mitochondrial membrane potential experiment showed that compound 2-3f could induce the decrease of mitochondrial membrane potential and the fluorescence confocal experiment of LC3 protein. The results also showed that compound 2-3f could increase the LC3 expression of autophagy marker protein. The mechanism of the effect of 2-3f on tumor cells is to induce autophagy. 2. Antimicrobial peptides are a novel antibacterial compound with wide antibacterial spectrum and low resistance. The purpose of the design and synthesis of small molecular cationic antimicrobial peptide mimics is to develop new antimicrobial candidate drugs. A total of 26 small cationic antimicrobial peptide simulators were synthesized by introducing triazole ring into antimicrobial peptide mimics. The minimum inhibitory concentrations of these compounds against four sensitive strains were tested. The results showed that the antibacterial activity of compounds 3-5gr, 3-5hu, 3-5i, 3-5y and 3-5z were better. Continue to test the minimum inhibitory concentrations of these five compounds against four different types of drug-resistant strains (Klebsiella pneumoniae, NDM-1 producing Escherichia coli, methicillin-resistant Staphylococcus aureus and VRE vancomycin resistant Enterococcus), The results showed that the five compounds had good antimicrobial activity against drug-resistant bacteria. The results of erythrocyte hemolysis test showed that compound 3-5z had less erythrocytic hemolytic toxicity, and the plasma stability test showed that compound 3-5z had good stability in plasma. It is difficult to be decomposed by enzyme in plasma, and its minimum bactericidal concentration only doubled after 6 hours of plasma treatment.
【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914;R96

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