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深海冷泉来源真菌构巢曲霉和绳状篮状菌次级代谢产物及其生物活性研究
吕凤翊
Subtype硕士
Thesis Advisor王斌贵
2020-05-22
Degree Grantor中国科学院大学
Place of Conferral中国科学院海洋研究所
Degree Name理学硕士
Keyword冷泉真菌 次级代谢产物 抗菌活性 抗肿瘤活性
Abstract

自二十世纪开始,来自世界各地的科研工作者们陆续从海洋来源微生物中分离鉴定出数量庞大的次级代谢产物,这些天然来源的化合物大多具有特殊的化学骨架结构特征并且生物活性多种多样,不但能够为海洋微生物资源的开发利用提供科学的指导,同时这些新颖的结构骨架或化合物还可能在药物作用机制研究和新药研制工作中发挥重要作用。随着时间推移,更加极端生存环境中的微生物产生的次级代谢产物成为探索的一个重要方向。深海冷泉来源的微生物由于适应特殊的生长环境,具有独特的代谢途径和遗传背景,其生物种类和代谢产物的化学类型多样性丰富,发现具有应用价值、结构新颖化合物的几率更高。因此,本研究选取冷泉微生物这一特殊群体进行研究,旨在探索冷泉特殊环境中微生物次生代谢产物的分子多样性,发现活性较好的天然产物作为药物开发备选的先导化合物,以丰富药物先导化合物的来源。

本论文通过分离冷泉来源的样品得到真菌菌株,经过系统筛选,最终选定中国南海冷泉沉积物来源的真菌构巢曲霉SD-531Aspergillus nidulans SD-531)和绳状篮状菌SD-523Talaromyces funiculosus SD-523)两株真菌,对其进行了次级代谢产物分子结构鉴定和相关生物活性的探索。规模发酵产物的系统分离工作综合运用了多种层析技术和制备方式作为分离手段,以TLCHPLC作为检测手段,共有效分离并鉴定了34个单体化合物,发现4个新结构,结构类型涵盖了硫代二酮哌嗪、过氧化物、氧杂蒽酮、混源萜等。

从真菌构巢曲霉SD-531A. nidulans SD-531)中分离得到28个化合物(AK1*-AK28),之中有4个为新化合物,包含3个硫代二酮哌嗪类次级代谢产物(AK1*-AK3*)和1个过氧化物类次级代谢产物(AK4*)。从绳状篮状菌SD-523T. funiculosus SD-523)中分离得到6个已知化合物(TF1-TF6)。对获得的部分单体次级代谢产物进行了抗细菌、抗真菌以及抗肿瘤细胞活性测试。其中构巢曲霉SD-531中分离得到的硫代二酮哌嗪类化合物AK1*-AK3*AK5-AK7具有良好的抑制肺癌细胞株Huh 7.5的活性,IC50介于0.25-19.0 μmol/L之间。AK1*-AK1911株细菌和8株真菌也具有不同程度的抗菌活性,其中AK5AK8AK10的抗菌活性较为广谱且效果显著。

本论文通过对冷泉真菌规模发酵产物的系统分离及鉴定,获得了结构新颖的代谢产物,丰富了次级代谢产物的化学结构多样性,并对其相关活性进行了初步探索,为深海冷泉微生物的有效发掘和应用方式方法提供了一定的科学参考。

Other Abstract

Since the beginning of the 20th century, researchers at home and abroad have successively isolated a large number of secondary metabolites from marine fungi. Most of these natural compounds have special structural characteristics and diverse biological activities, which can not only provide scientific guidance for the development and utilization of marine microbial resources, but also play an important role in the mechanism research and new drug development. As time goes on, the secondary metabolites produced by microorganisms in more extreme living environment become an important focus of exploration. Cold spring microorganisms have unique metabolic pathway and genetic background due to their adaptation to special growth environment. For the abundant of diversities of biological species and chemical types of metabolites, it is more likely to find novel chemical structures with application values. Therefore, the study selected cold spring microorganism to study, in order to explore natural products with better activity as alternative lead compounds for drug development, so as to enrich sources of drug lead compounds.

In this paper, two cold-spring-derived fungi, Aspergillus nidulans SD-531 and Thalanomyces funiculosus SD-523, were selected to find their secondary metabolites and explore their biological activities. In the systematic separation of crude extracts, a variety of chromatography methods were used as the separation methods and TLC and HPLC analysis were used as detection methods. Including thiodiletpiperazine, peroxides, oxaxanthone, terpenes, etc, thierty-four compounds were isolated and identified, while four new structures were found.

Twenty eight compounds (AK1*-AK28) were isolated from fungus A. nidulans SD-531. Four of them were new compounds, including three thiodiketpiperazines (AK1*-AK3*) and one peroxide (AK4*). Six known compounds (TF1-TF6) were isolated from T. funiculosus SD-523. Some of the isolated compounds were evaluated for antibacterial, antifungi and antitumor activities. Compounds AK1*-AK3* and AK5-AK7 had cytotoxic activity against the tumor cell line Huh 7.5, with IC50 values ranging from 0.25-19.0 μmol/L. AK1*-AK19 had antimicrobial activities against 11 bacterium and 8 fungi with MIC values ranging from 0.5-64 μg/mL, while AK5, AK8 and AK10 displayed broad spectrum and significant activities among the tested samples.

In this paper, the new compounds were isolated and identified from the extracts of cold spring fungi. The diversity of secondary metabolites was enriched and the activities of the compounds were preliminarily explored. It provides a scientific reference for the effective exploration and application of cold spring microbial resources.

Language中文
Document Type学位论文
Identifierhttp://ir.qdio.ac.cn/handle/337002/164687
Collection实验海洋生物学重点实验室
Recommended Citation
GB/T 7714
吕凤翊. 深海冷泉来源真菌构巢曲霉和绳状篮状菌次级代谢产物及其生物活性研究[D]. 中国科学院海洋研究所. 中国科学院大学,2020.
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