两株珊瑚共附生真菌的次生代谢产物研究
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摘要
珊瑚代谢产物种类繁多、结构新颖,是海洋天然产物三大来源之一。其共附生微生物可能是这些代谢产物的真正产生者。为了寻找新颖结构的活性化合物,本论文采用化学与生物学相集成的筛选方法,开展了对珊瑚共附生真菌的筛选及2株共附生真菌的次生代谢产物的研究工作。内容包括：珊瑚共附生真菌的分离与天才菌株的筛选；发酵菌株发酵条件的优化及细胞毒活性成分的追踪分离；单体化合物的结构解析；单体化合物的细胞毒活性初步评价。
对采自海南陵水、三亚、临高、万宁港、广西涠洲、广东湛江的珊瑚样品中分离获得198株共附生真菌,运用集成化学和生物学的筛选方法最终确定5株为天才菌株,并选定其中的两株Aspergillus versicolor LCJ-5-4和Penicillium sp. gxwz406作为本论文的目标菌株。对这两株目标菌株发酵条件做了优化,确定了优化培养基和培养条件并进行了大量发酵,得到发酵产物(粗提物)；采用薄层色谱、硅胶柱色谱、Sephadex LH-20柱色谱、反相高效液相色谱等手段分离其中的活性化合物；通过解析波谱数据并结合理化常数阐明了21个化合物的结构。其中从杂色曲霉Aspergillus versicolor LCJ-5-4的发酵产物中分离鉴定了16个化合物：versitides A-C (1-3), cottoquinazolines B-D (4-6), glyantrypine (7), (Z)-5-(2,3-dihydroxybutylidene)furan-2(5H)-one (8), (E)-5-(2,3-dihydroxybutylidene)furan-2(5H)-one(9),-tetraorcinol (10), diorcinol (11), cordyol C (12), versicolorin B (13), 1,3,6,8-tetrahydroxy-9,10-anthraquinone (14), versicol (15), averufanin (16);从青霉Penicillium sp. gxwz406的发酵产物分离鉴定了5个化合物：S(-)-2-(2-hydroxy propanamido)benzamide (17), R(+)-chrysogine (18),2-pyruvylaminobenzamide (19), nicotinamide (20), and 2',3'-dihydrosorbicillin (21)。其中9个化合物(1-6、8-10)为新化合物!
运用MTT法对分离获得的单体化合物的抗肿瘤活性进行了初步评价。结果表明：菌株Penicillium sp. gxwz406的主产物化合物19对两种癌细胞(Hela和P388)都表现较弱的活性,IC50分别为10.6和15.6μM。
综上所述,本文采用集成筛选的方法获得5株珊瑚共附生的天才菌株,从其中2株真菌的发酵产物中分离鉴定了21个单体化合物,其中9个为新化合物。说明我们集成筛选寻找活性次生代谢产物的的方法是可行的,为抗肿瘤药物的研究提供了新化合物及其资源菌株。
Because of the special living environment, coral possess distinct and complex metabolic capabilities, resulting in wide diversity of their secondary metabolites in chemical structure and biological activity. Most of these secondary metabolites are possibly resulted from their symbiotic microorganisms. This thesis describes the screening of symbiotic fungi and studies on the secondary metabolites produced by two selected talented fungal strains from coral. Studies include isolation of symbiotic fungi from coral samples, screening of talented strains, optimization of fermentation, bioassay-guided fractionation, structural elucidation and cytotoxicity evaluation.
Five talented strains were obtained by integrated cytotoxic and chemical screening methods from 168 fungi isolated from corals collected from Linshui, Sanya, Lingao, Wanninggang, Weizhou, Zhanjiang, China. Because of cytotoxicity and a series HPLC peaks with similar UV absorption, Aspergillus versicolor LCJ-5-4 and Penicillium sp. gxwz406 were selected as working strains for further study of secondary metabolites. Guided by bioactivity, the active fractions were subjected to chromatography over silica gel, Sephadex LH-20 and prepared TLC, and preparative HPLC to afford 16 compounds from Aspergillus versicolor LCJ-5-4. By the same procedure,5 compounds were isolated and identified from Penicillium sp. gxwz406. By means of spectroscopic and chemical methods, their structures were elucidated as: aspertides A-C (1-3), cottoquinazolines B-D (4-6), glyantrypine (7), (Z)-5-(2,3-dihydroxybutylidene)furan-2(5H)-one(8), (E)-5-(2,3-dihydroxybutylidene) furan-2(5H)-one (9), tetraorcinol (10), diorcinol (11), cordyol C (12), versicolorin B (13), 1,3,6,8-Tetrahydroxy-9,10-anthraquinone (14), versicol (15), averufanin (16); S(-)-2-(2-hydroxypropanamido)benzamide (17),R(+)-chrysogine (18),2-pyruvyl aminobenzamide (19), nicotinamide (20), and 2',3'-dihydrosorbicillin (21)。Among them, compounds 1-6 and 8-10 are new compounds.
The cytotoxicity of these compounds against two cancer cell lines was evaluated by MTT method. Compound 19, one of the main metabolites from Penicillium sp. gxwz406 exhibited cytotoxicity against P388 and Hela cells with IC50 values of 10.6μM and 15.6μM, respectively.
In a word, nine new compounds together with twelve known ones were isolated and identified from the two symbiotic fungi with corals. Studies mentioned above provide novel structures for searching new leading compounds and microbial resources for further study and it proves the method we used is effective in finding new active compounds.
对采自海南陵水、三亚、临高、万宁港、广西涠洲、广东湛江的珊瑚样品中分离获得198株共附生真菌,运用集成化学和生物学的筛选方法最终确定5株为天才菌株,并选定其中的两株Aspergillus versicolor LCJ-5-4和Penicillium sp. gxwz406作为本论文的目标菌株。对这两株目标菌株发酵条件做了优化,确定了优化培养基和培养条件并进行了大量发酵,得到发酵产物(粗提物)；采用薄层色谱、硅胶柱色谱、Sephadex LH-20柱色谱、反相高效液相色谱等手段分离其中的活性化合物；通过解析波谱数据并结合理化常数阐明了21个化合物的结构。其中从杂色曲霉Aspergillus versicolor LCJ-5-4的发酵产物中分离鉴定了16个化合物：versitides A-C (1-3), cottoquinazolines B-D (4-6), glyantrypine (7), (Z)-5-(2,3-dihydroxybutylidene)furan-2(5H)-one (8), (E)-5-(2,3-dihydroxybutylidene)furan-2(5H)-one(9),-tetraorcinol (10), diorcinol (11), cordyol C (12), versicolorin B (13), 1,3,6,8-tetrahydroxy-9,10-anthraquinone (14), versicol (15), averufanin (16);从青霉Penicillium sp. gxwz406的发酵产物分离鉴定了5个化合物：S(-)-2-(2-hydroxy propanamido)benzamide (17), R(+)-chrysogine (18),2-pyruvylaminobenzamide (19), nicotinamide (20), and 2',3'-dihydrosorbicillin (21)。其中9个化合物(1-6、8-10)为新化合物!
运用MTT法对分离获得的单体化合物的抗肿瘤活性进行了初步评价。结果表明：菌株Penicillium sp. gxwz406的主产物化合物19对两种癌细胞(Hela和P388)都表现较弱的活性,IC50分别为10.6和15.6μM。
综上所述,本文采用集成筛选的方法获得5株珊瑚共附生的天才菌株,从其中2株真菌的发酵产物中分离鉴定了21个单体化合物,其中9个为新化合物。说明我们集成筛选寻找活性次生代谢产物的的方法是可行的,为抗肿瘤药物的研究提供了新化合物及其资源菌株。
Because of the special living environment, coral possess distinct and complex metabolic capabilities, resulting in wide diversity of their secondary metabolites in chemical structure and biological activity. Most of these secondary metabolites are possibly resulted from their symbiotic microorganisms. This thesis describes the screening of symbiotic fungi and studies on the secondary metabolites produced by two selected talented fungal strains from coral. Studies include isolation of symbiotic fungi from coral samples, screening of talented strains, optimization of fermentation, bioassay-guided fractionation, structural elucidation and cytotoxicity evaluation.
Five talented strains were obtained by integrated cytotoxic and chemical screening methods from 168 fungi isolated from corals collected from Linshui, Sanya, Lingao, Wanninggang, Weizhou, Zhanjiang, China. Because of cytotoxicity and a series HPLC peaks with similar UV absorption, Aspergillus versicolor LCJ-5-4 and Penicillium sp. gxwz406 were selected as working strains for further study of secondary metabolites. Guided by bioactivity, the active fractions were subjected to chromatography over silica gel, Sephadex LH-20 and prepared TLC, and preparative HPLC to afford 16 compounds from Aspergillus versicolor LCJ-5-4. By the same procedure,5 compounds were isolated and identified from Penicillium sp. gxwz406. By means of spectroscopic and chemical methods, their structures were elucidated as: aspertides A-C (1-3), cottoquinazolines B-D (4-6), glyantrypine (7), (Z)-5-(2,3-dihydroxybutylidene)furan-2(5H)-one(8), (E)-5-(2,3-dihydroxybutylidene) furan-2(5H)-one (9), tetraorcinol (10), diorcinol (11), cordyol C (12), versicolorin B (13), 1,3,6,8-Tetrahydroxy-9,10-anthraquinone (14), versicol (15), averufanin (16); S(-)-2-(2-hydroxypropanamido)benzamide (17),R(+)-chrysogine (18),2-pyruvyl aminobenzamide (19), nicotinamide (20), and 2',3'-dihydrosorbicillin (21)。Among them, compounds 1-6 and 8-10 are new compounds.
The cytotoxicity of these compounds against two cancer cell lines was evaluated by MTT method. Compound 19, one of the main metabolites from Penicillium sp. gxwz406 exhibited cytotoxicity against P388 and Hela cells with IC50 values of 10.6μM and 15.6μM, respectively.
In a word, nine new compounds together with twelve known ones were isolated and identified from the two symbiotic fungi with corals. Studies mentioned above provide novel structures for searching new leading compounds and microbial resources for further study and it proves the method we used is effective in finding new active compounds.
引文
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[5]张敏等.海绵共附生微生物次级代谢产物的研究进展[J].中国海洋大学学报.2007年5月37(3)：377～384.
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[9]司书毅,张月琴.药物筛选——方法与实践化学[M].工业出版社,2007,pp.411.
[1]P. Skehan, R. Storeng, D. Scudiero, et al. New Colorimetric Cytotoxicity Assay for Anticancer-Drug Screening[J]. J. Natl. Cancer Inst.1990,82,1107.
[2]S. Grabley, R. Thiericke, Drug discovery from nature[M]. Springer,2000, pp.124.
[3]司书毅,张月琴.药物筛选——方法与实践化学[M].工业出版社,2007,pp.411.
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