【作者】 陈道煌；

【导师】 陈河如；

【作者基本信息】 汕头大学 ， 药物化学， 2010， 硕士

【摘要】 Loloatin C是从热带海洋细菌的实验室培养物中发现、分离得到的环十肽化合物,大量实验结果显示它对革兰氏阳性菌及阴性菌均表现出很好的活性。前人通过滑动图窗的方法将Loloatin C分为南、中、北三个环六肽,成功合成得到环肽,并进一步进行药敏实验,结果发现药核是包含–D-Tyr-Pro-Trp-D-Phe-片段的环状化合物。我们采用固相及液相合成法,设计并合成一系列包含–D-Tyr-Pro-Trp-D-Phe-片段的假环肽化合物,期望得到活性更好的假环肽化合物。为了初步了解Loloatin C的抑菌机制,我们研究了未经处理及在CCCP预处理情况下Loloatin C对大肠杆菌生长的抑制情况,以及以乳糖为诱导剂作用下大肠杆菌的β-半乳糖苷酶的活性。研究结果:(1)成功合成5个线性多肽前体(S1-1、S1-2、S、S2-1、S2-2)及3个假环肽化合物(C1-2、C2-1、C2-2),线性多肽前体的总产率在40%左右;而假环肽的总产率较低,大约为2%左右;(2)大肠杆菌在CCCP的作用下其存活率明显提高,从而推断Loloatin C抗菌肽不会因致病细菌的主动外排系统而产生耐药性的问题。(3)实验菌株大肠杆菌的β-半乳糖苷酶活性随着多肽药物Loloatin C的作用浓度的增加而相应地增强。更多还原

【Abstract】 Loloatin C was discovered and separated from tropical ocean bacterial laboratory, which is a cyclodecapeptide compound. Many experiments have shown that Loloatin C has remarkable activity to G+ and G- bacteria. Three cyclohexapeptides (named north, middle, and south cyclohexapeptide) narrowed down from Loloatin C by sliding window were figured out and synthesized. Antimicrobial screening conformed that the pharmacophore of Loloatin C contains structure of–D-Tyr-Pro-Trp-D-Phe-. Based on these results, we design and synthesize series of pseudocyclicpeptides, which contain–D-Tyr-Pro-Trp-D-Phe-, expecting to get more active compounds.In order to study the antibacterial mechanism of Loloatin C, growth inhibition of loloatin C to E. coli was investigated under the existence or without the existence of CCCP. The activity ofβ-galactose glycosidase when Loloatin C interacted with E. coli was also studied by using lactose as substrate.The following results have been obtained: (1) Five linear precursor peptides (S1-1, S1-2, S, S2-1, S2-2)were synthesized and the overall yields were about 40%; three pseudo cyclopeptides (C1-2, C2-1, C2-2) were obtained but the overall yield were low, only 2%; (2) More E.coli bacteria survive under the existence of CCCP, which we can infer that the problem of resistance won’t happen due to the excessive expression of efflux system of bacteria. Besides, as the concentration of Loloatin C increases, the activity ofβ-galactose glycoside from E.coli gets stronger.更多还原