三株海洋真菌活性次生代谢产物及其碱调节研究
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摘要
海洋真菌是活性海洋天然产物的重要来源。由于海洋真菌生活在寡营养，弱碱的海水环境中，可能形成独特代谢机制，产生有别于陆生真菌的次生代谢产物，近年来逐渐成为研究的热点之一。为了寻找海洋来源真菌中的“Talented strains”和结构新颖的活性代谢产物，本论文对分离自南海直针小尖柳珊瑚Muricellaabnormalis、海南文昌头苑红树植物海漆Excoecaria agallocha根部样品和东营黄河入海口滩涂植物蒙古鸦葱Scorzonera mongalica三种不同海洋来源样品中分得的真菌，通过化学和生物学相结合的筛选模式，从中获得3株海洋来源“Talentedstrains”；对这3株“Talented strains”进行系统的次生代谢产物研究，并选择其中的一株“Talented strains”进行了碱胁迫发酵培养的初步研究。
取得的主要研究成果有：
1.海洋天才真菌的筛选。从实验室菌株库提供的10株海洋来源真菌为筛选对象。以MCF-7肿瘤细胞增殖抑制、抑菌和抗炎试验作为生物活性筛选模型，TLC薄层色谱和HPLC指纹图谱作为化学筛选模型，采用生物活性和化学评价相结合的集成筛选模式，最终获得3株海洋“Talented strains”，并对3株“Talentedstrains”碱胁迫发酵培养条件进行探索研究。
2.对3株海洋“Talented strains”次生代谢产物进行系统研究。包括对“Talented strains”进行发酵条件摸索，如培养基、发酵天数、碱源及盐度等，选择最佳培养条件进行大发酵，获得发酵浸膏。通过薄层色谱、硅胶柱色谱、Sephadex LH-20柱色谱、反相高效液相色谱等分离方法，从3株海洋天才真菌次生代谢产物中，应用现代波谱技术(UV，IR，NMR，MS，X-Ray等)和化学方法分离鉴定了76个单体化合物的化学结构。其中新化合物23个：从团青霉Penicillium commune518#的代谢产物中获得了12个新的芳香聚酮类化合物（1–12）；从扩张青霉Penicillium expansum091006的代谢产物中得到1个新的没药烷型倍半萜衍生物（25）和1个新的二聚苯酚类衍生物（29）；从互隔交链孢菌Alternaria alternata007#的代谢产物中得到4个新的混源萜类化合物（40–43）。已知化合物的结构类型涉及苯衍生物、混源萜、吲哚生物碱类化合物及核苷等。运用体外生物活性筛选模型，初步评价了单体化合物的肿瘤细胞增殖抑制活性、抑菌活性、抗炎活性、细菌群体感应活性和逆转多药耐药活性等。肿瘤细胞增殖抑制活性测试表明：甲苯酚三聚体类化合物21–24对HL-60有中等强度的抑制活性，IC50分别为15.7，5.4，18.2和20.8μM；此外化合物22对肿瘤细胞株A549也有较强的抑制活性，IC50为1.9μM。抗炎活性结果表明：对单体化合物进行体外NF-κB通路抗炎抑制活性筛选时，化合物4、44和47有弱的抑制活性，IC50分别为45.9、52.0和41.8μM。抑菌活性结果表明：芳香聚酮类化合物4、5、9和12对白色念珠菌具有抑制作用，MIC分别为15.7、16.4、25.8和23.8μM；化合物1、4–6、9、12、49–51对大肠杆菌具有抑制作用，MIC分别为10.6、3.9、4.1、17.1、6.4、23.8、14.5、2.9、2.6μM；化合物1、4和6对铜绿假交替单胞菌具有抑制作用，MIC分别为10.6、15.7、17.1μM；化合物49和66对金黄色葡萄球菌具有抑制作用，MIC分别为28.9、29.1μM。
3.初步研究了碱胁迫对海洋来源真菌次生代谢产物化学多样性的影响。发现不同碱源、不同灭菌步骤对海洋真菌次生代谢产物影响较大。从互隔交链孢菌Alternaria alternata007#碱胁迫发酵产物中分离鉴定新化合物5个(61-65),证实了碱胁迫培养发酵是增加海洋真菌化学多样性的有效途径之一。
综上所述，本文通过对三株海洋“Talented strains”和一株海洋细菌活性次生代谢产物的系统研究，获得了76个单体化合物，其中新化合物23个、活性化合物21个；证实了碱胁迫能够增加海洋真菌的化学多样性，产生系列新的活性代谢产物，并为海洋真菌发酵培养策略研究提供了新的思路。
Marine fungi are a kind of important source for active marine natural products.Because of its specificity of living oligotrophic, weak alkaline environment, marinefungi may have unique secondary metabolic pathways and produce the novelsecondary metabolites. In recent years, marine fungi have gradually become one ofthe hot. By integrated biological and chemical screening methods, three talentedstrains were obtained from different marine-derived samples. Optimizations offermentation condition for talented strains were systematically studied. Furthermore,we attempted to culture one talented strain under alkaline stress, and studied thedifferences in the compounds skeleton of fermentation products compared to thenormal pH culture conditions.
Our study focused on the new secondary metabolites of marine fungi underalkaline stress, and includes the following three parts:
1. Screening for the marine-derived talented strains.
10strains of marine fungi from coral-associated sample in South China Sea, plantsof mangrove forest in Hainan and seaside plants in the Yellow River delta have beenscreened. The EtOAc extracts of these fungi were evalassesed with the combinatorymethod based on chemical and bioactive screening. Three of them were confirmed asmarine-derived talented strains with cytotoxicity or antibiotic or anti-inflammatoryactivities, while one talented strain was chosen to culture under alkaline stress. Inaddition, we carried out the preliminary study of the fermentation under alkalinestress.
2. Study on secondary metabolites of three talented strains under weak alkalineenvironment
Optimizations of fermentation condition for talented strains were determinedbased on the research of effect of different conditions, such as medium, fermentationtime, alkali source and salinity. Three strains were fermented separately, and then thewhole broths were extracted with EtOAc in order to get active extracts. These extractswould be subjected to extensive silica gel column chromatography, Sephadex LH-20and HPLC purifications. After processing,76compounds were isolated from these three marine-derived talented strains and identified by means of detailedspectroscopic analysis (such as UV, IR, NMR, MS, X-Ray, etc) and chemicalmethods. Among them,25compounds were new ones, including twelve new aromaticpolyketides compounds (1–12) obtained from P. commune518#, one new phenolicbisabolane sesquiterpenoid (25) and one new diphenyl ether derivative (29) from P.expansum091006, Four new meroterpenoids,(40–43) from A. alternata007#. Theknown compounds refer to phenolic compounds, meroterpenoids, indole alkaloids andnucleosides. Compounds21–24exhibited moderate cytotoxicity against HL-60cellline with IC50values of15.7,5.4,18.2and20.8μM, respectively; Compound22alsohad significant cytotoxicity against A549cell line with an IC50value of1.9μM.Compounds4,44and47exhibited weak anti-inflammatory on the transcriptionalactivity of NF-κB in stimulated RAW264.7cells with IC50values of45.9,52.0and41.8μM, respectively. Compounds1,4–6,9and12showed antibiotic activity againstC. albicans, E. coli, P. aeruginosa or S.aureus with MIC values ranged from2.6μMto29.1μM.
3. Preliminary evaluation of the effect of alkaline stress on chemical diversity ofsecondary metabolites of marine fungal strains
To further research the effect of alkaline stress on chemical diversity of secondarymetabolites of marine fungal strains, the secondary metabolites of A. alternata007#under alkaline stress culture condition were studied by comparing the retention timeof their production. And we found that the alkali sources and the steps of sterilizationplayed an important part in the formation of secondary metabolites of this fungus. Thestrain A. alternata007#cultured under alkaline stress was found to produce6different meroterpenoids, five of which (61–65) were new ones. More importantly, itwas established that marine fungi could increase the chemical diversity of secondarymetabolites under alkaline stress.
Summarily,23new compounds and53known ones were obtained in this work, and21of these compounds showed cytotoxic, anti-inflammatory and antibiotic activities.
取得的主要研究成果有：
1.海洋天才真菌的筛选。从实验室菌株库提供的10株海洋来源真菌为筛选对象。以MCF-7肿瘤细胞增殖抑制、抑菌和抗炎试验作为生物活性筛选模型，TLC薄层色谱和HPLC指纹图谱作为化学筛选模型，采用生物活性和化学评价相结合的集成筛选模式，最终获得3株海洋“Talented strains”，并对3株“Talentedstrains”碱胁迫发酵培养条件进行探索研究。
2.对3株海洋“Talented strains”次生代谢产物进行系统研究。包括对“Talented strains”进行发酵条件摸索，如培养基、发酵天数、碱源及盐度等，选择最佳培养条件进行大发酵，获得发酵浸膏。通过薄层色谱、硅胶柱色谱、Sephadex LH-20柱色谱、反相高效液相色谱等分离方法，从3株海洋天才真菌次生代谢产物中，应用现代波谱技术(UV，IR，NMR，MS，X-Ray等)和化学方法分离鉴定了76个单体化合物的化学结构。其中新化合物23个：从团青霉Penicillium commune518#的代谢产物中获得了12个新的芳香聚酮类化合物（1–12）；从扩张青霉Penicillium expansum091006的代谢产物中得到1个新的没药烷型倍半萜衍生物（25）和1个新的二聚苯酚类衍生物（29）；从互隔交链孢菌Alternaria alternata007#的代谢产物中得到4个新的混源萜类化合物（40–43）。已知化合物的结构类型涉及苯衍生物、混源萜、吲哚生物碱类化合物及核苷等。运用体外生物活性筛选模型，初步评价了单体化合物的肿瘤细胞增殖抑制活性、抑菌活性、抗炎活性、细菌群体感应活性和逆转多药耐药活性等。肿瘤细胞增殖抑制活性测试表明：甲苯酚三聚体类化合物21–24对HL-60有中等强度的抑制活性，IC50分别为15.7，5.4，18.2和20.8μM；此外化合物22对肿瘤细胞株A549也有较强的抑制活性，IC50为1.9μM。抗炎活性结果表明：对单体化合物进行体外NF-κB通路抗炎抑制活性筛选时，化合物4、44和47有弱的抑制活性，IC50分别为45.9、52.0和41.8μM。抑菌活性结果表明：芳香聚酮类化合物4、5、9和12对白色念珠菌具有抑制作用，MIC分别为15.7、16.4、25.8和23.8μM；化合物1、4–6、9、12、49–51对大肠杆菌具有抑制作用，MIC分别为10.6、3.9、4.1、17.1、6.4、23.8、14.5、2.9、2.6μM；化合物1、4和6对铜绿假交替单胞菌具有抑制作用，MIC分别为10.6、15.7、17.1μM；化合物49和66对金黄色葡萄球菌具有抑制作用，MIC分别为28.9、29.1μM。
3.初步研究了碱胁迫对海洋来源真菌次生代谢产物化学多样性的影响。发现不同碱源、不同灭菌步骤对海洋真菌次生代谢产物影响较大。从互隔交链孢菌Alternaria alternata007#碱胁迫发酵产物中分离鉴定新化合物5个(61-65),证实了碱胁迫培养发酵是增加海洋真菌化学多样性的有效途径之一。
综上所述，本文通过对三株海洋“Talented strains”和一株海洋细菌活性次生代谢产物的系统研究，获得了76个单体化合物，其中新化合物23个、活性化合物21个；证实了碱胁迫能够增加海洋真菌的化学多样性，产生系列新的活性代谢产物，并为海洋真菌发酵培养策略研究提供了新的思路。
Marine fungi are a kind of important source for active marine natural products.Because of its specificity of living oligotrophic, weak alkaline environment, marinefungi may have unique secondary metabolic pathways and produce the novelsecondary metabolites. In recent years, marine fungi have gradually become one ofthe hot. By integrated biological and chemical screening methods, three talentedstrains were obtained from different marine-derived samples. Optimizations offermentation condition for talented strains were systematically studied. Furthermore,we attempted to culture one talented strain under alkaline stress, and studied thedifferences in the compounds skeleton of fermentation products compared to thenormal pH culture conditions.
Our study focused on the new secondary metabolites of marine fungi underalkaline stress, and includes the following three parts:
1. Screening for the marine-derived talented strains.
10strains of marine fungi from coral-associated sample in South China Sea, plantsof mangrove forest in Hainan and seaside plants in the Yellow River delta have beenscreened. The EtOAc extracts of these fungi were evalassesed with the combinatorymethod based on chemical and bioactive screening. Three of them were confirmed asmarine-derived talented strains with cytotoxicity or antibiotic or anti-inflammatoryactivities, while one talented strain was chosen to culture under alkaline stress. Inaddition, we carried out the preliminary study of the fermentation under alkalinestress.
2. Study on secondary metabolites of three talented strains under weak alkalineenvironment
Optimizations of fermentation condition for talented strains were determinedbased on the research of effect of different conditions, such as medium, fermentationtime, alkali source and salinity. Three strains were fermented separately, and then thewhole broths were extracted with EtOAc in order to get active extracts. These extractswould be subjected to extensive silica gel column chromatography, Sephadex LH-20and HPLC purifications. After processing,76compounds were isolated from these three marine-derived talented strains and identified by means of detailedspectroscopic analysis (such as UV, IR, NMR, MS, X-Ray, etc) and chemicalmethods. Among them,25compounds were new ones, including twelve new aromaticpolyketides compounds (1–12) obtained from P. commune518#, one new phenolicbisabolane sesquiterpenoid (25) and one new diphenyl ether derivative (29) from P.expansum091006, Four new meroterpenoids,(40–43) from A. alternata007#. Theknown compounds refer to phenolic compounds, meroterpenoids, indole alkaloids andnucleosides. Compounds21–24exhibited moderate cytotoxicity against HL-60cellline with IC50values of15.7,5.4,18.2and20.8μM, respectively; Compound22alsohad significant cytotoxicity against A549cell line with an IC50value of1.9μM.Compounds4,44and47exhibited weak anti-inflammatory on the transcriptionalactivity of NF-κB in stimulated RAW264.7cells with IC50values of45.9,52.0and41.8μM, respectively. Compounds1,4–6,9and12showed antibiotic activity againstC. albicans, E. coli, P. aeruginosa or S.aureus with MIC values ranged from2.6μMto29.1μM.
3. Preliminary evaluation of the effect of alkaline stress on chemical diversity ofsecondary metabolites of marine fungal strains
To further research the effect of alkaline stress on chemical diversity of secondarymetabolites of marine fungal strains, the secondary metabolites of A. alternata007#under alkaline stress culture condition were studied by comparing the retention timeof their production. And we found that the alkali sources and the steps of sterilizationplayed an important part in the formation of secondary metabolites of this fungus. Thestrain A. alternata007#cultured under alkaline stress was found to produce6different meroterpenoids, five of which (61–65) were new ones. More importantly, itwas established that marine fungi could increase the chemical diversity of secondarymetabolites under alkaline stress.
Summarily,23new compounds and53known ones were obtained in this work, and21of these compounds showed cytotoxic, anti-inflammatory and antibiotic activities.
引文
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