两株海洋微生物中的活性吲哚生物碱研究
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摘要
海洋微生物生存环境复杂特殊,其次生代谢产物结构新颖、种类繁多,是新结构活性化合物的重要来源。为了寻找结构新颖的活性化合物,本论文采用活性追踪的方法开展了对海洋放线菌和海洋细菌次生代谢产物的研究工作。内容主要包括：活性菌株的筛选及初步评价,抗肿瘤活性成分的追踪分离,单体化合物的结构解析,化合物抗肿瘤及抑菌活性的初步评价。
经研究发现,多种海洋生物包括海绵、被囊动物、红藻以及海洋共附生微生物等都可以产生结构新颖的吲哚生物碱类化合物,该类化合物是海洋来源生物碱最重要的组成部分。这些海洋来源的吲哚类生物碱与陆生来源的相比不仅具有结构骨架的复杂性,而且存在卤素取代的现象。目前为止,海洋来源吲哚类生物碱具有细胞毒活性、抗病毒、抗微生物、抗炎、抑制拓扑异构酶Ⅰ等多种生物活性,因此该类化合物构效关系的研究广泛受到科学家们的关注。
将分离自青岛沿海及南海红树林样品的126株放线菌和细菌进行集成筛选。首先采用SRB法,以小鼠白血病P388肿瘤细胞为筛选模型进行体外抗肿瘤活性的筛选,然后结合HPLC指纹图谱及薄层色谱进行化学筛选,得到具有较强细胞毒活性的菌株4株,最终确定了1株主产吲哚咔唑生物碱、细胞毒活性较强的链霉菌Streptomyces sp. FMA作为进一步研究的目标菌株。同时,为了开发病原菌资源,选择了以吲哚生物碱为主要次生代谢产物并可产生多种高丝氨酸内酯(AHLs)信号分子的致病菌迟缓爱德华氏菌(E. tarda) LTB-4作为另一目标菌株。
以迟缓爱德华氏菌(E. tarda)和海洋链霉菌Streptomyces sp. FMA为研究对象,对发酵产物运用萃取,薄层层析,正相、反相硅胶柱层析,LH-20凝胶柱层析,反相高压液相等多种化学的分离纯化手段,进行活性次生代谢产物的追踪分离。从E. tarda LTB-4的次生代谢产物中分离得到15个单体化合物(1-15),从Streptomyces sp. FMA的次生代谢产物中分离得到13个单体化合物(16-28)。继而,利用理化性质和波谱学方法(IR,UV,MS,NMR等)结合化学反应的方法阐述了28个化合物的化学结构(化合物结构及名称参见Table 1),其中新天然产物2个(1,2),新化合物2个(16,17)。所得化合物的结构类型包括：吲哚咔唑类化合物(16-22)、简单吲哚类生物碱(1-10,23)、黄酮类(11)、苯类衍生物(12-13,24-26)、核苷碱基(14-15)、呋喃类(27)和不饱和内酯类(28)。由此可见,吲哚类生物碱是Streptomyces sp. FMA和E. tarda次生代谢产物的主要结构类型。
通过气相色谱和质谱连用(GC-MS)的测试手段,对迟缓爱德华氏菌(E. tarda)胞外的5种酰化高丝氨酸内酯(AHLs)信号分子进行了结构鉴定,分别为C4-HSL、C6-oxo-HSL、C8-HSL、C8-oxo-HSL和C10-HSL,为该类细菌信号传导的研究提供了依据。
利用SRB法、MTT法及药敏纸片法对分离获得的单体化合物的抗肿瘤、抗菌活性分别进行了初步评价。筛选出了3个抗肿瘤化合物(2、16、18)；1个抗菌活性化合物(12)。其中,化合物2对A549的IC50为6.24μM,化合物16对HL60和A549细胞的IC50分别为4.97μM和2.01μM化合物18对P388和Hela细胞的IC50分别为1.37μM和5.06μM；化合物12对产气杆菌(Clostridium perfringens)和大肠杆菌(E. coli)均有抑制作用,其最小抑菌浓度(MIC)分别为31.25μg/mL和37.5μg/mL。
综上,本文对两株海洋微生物的次生代谢产物进行了系统研究,共分离鉴定了28个化合物,包括天然来源的新吲哚生物碱2个,新吲哚咔唑类生物碱2个,较高抗肿瘤活性化合物3个；并且提供了1株能特征产生吲哚咔唑类生物碱的海洋链霉菌和1株可高产吲哚类生物碱的海洋细菌。这一研究丰富了海洋天然产物的结构类型,同时也为抗肿瘤药物的筛选提供了活性化合物及活性菌株。
Because of the special ecological environment, marine-derived microorganisms possess distinct and complex metabolic capabilities, resulting in wide diversity of their secondary metabolites in chemical structure and biological activity. Thus, bacterium and actinomycetes become important resources of active lead compounds. This thesis describes the bioactive constituents from marine-derived bacterium E. tarda and Streptomycetes sp. FMA. The work includes screening aimed strains, fermentation studies, bioassay-guided fractionation, structural elucidation, preliminary evaluation for anti-tumor and anti-bacterial activities of pure compounds.
A variety of marine sources including sponges, tunicates, red alga, acorn worms, and symbiotic bacteria have been shown to generate indole alkaloids, which represent the largest number and most complicated of the marine alkaloids (1/4 of total alkaloids). The alkaloids obtained from marine organisms frequently possess novel frameworks while in other cases terrestrially related compounds clearly exist. Marine metabolites often possess complexities such as halogen substituents. Their structure elucidation, chemical modification, stereochemistry, synthesis, and pharmacology have received a great deal of interdisciplinary attention from areas of research other than chemistry and include pharmacology, physiology, and medicine.
Four active strains were picked out based on integrated screening that combines the cytotoxicity against P388 cells with chemodiversity (HPLC and TLC properties) of the metabolites from 126 marine-derived actinomycetes and bacterias. Among them, Streptomycetes sp. FMA was selected for further study of their secondary metabolites exhibited high anti-tumor activities and a series of HPLC peaks with similar UV absorption to those of indolocarbazoles. Besides, the gram-negative bacterium E. tarda, pathogen of fish, animal and human was also found to display a series of HPLC peaks with similar UV absorption to those of indolalkaloids. In order to investigate the potential of pathogens for drug discovery, the secondary metabolites and AHLs of E. tarda were studied as well.
140L-scale fermentation of the E. tarda and 100L-scale fermentation of the Streptomycetes sp. FMA were performed to obtain the active extracts, respectively. By means of chromatography over silica gel column, Sephadex LH20, preparative TLC and semi-preparative HPLC, fifteen (1-15) and thirteen compounds (16-28) were isolated from E. tarda and Streptomycetes sp. FMA, respectively. Basing on their physico-chemical properties and spectral data (IR, UV, MS, NMR, etc.), twenty eight compounds were elucidated as 1,1-(3,3'-diindolyl)-2-phenylethane (1),3-(1H-indol-3-yl)-2,3'-bi-(1H-indole) (2),2,2-di(3-indolyl)-3-indolone (3), tri(1H-indol-3-yl) methane (4),2-[2,2-bis(1H-indol-3-yl)]ethylphenylamine (5), bis-(1H-indol-3-yl) phenylmethane (6),4-di(1H-indol-3-yl) methylphenol (7), (2S)-3,3-bis-(1H-indol-3-yl) propane-1,2-diol (8), Indole (9),2-(1H-indol-3-yl) ethanol (10), genistein (11), (2-Naphthyl)phenylamine (12), benzeneethanol (13), uracil (14), thymine (15), streptocarbazole A (16), streptocarbazole B (17),3'-(S)-epi-K252a (18),3'-(S)-K252a (19), RK 286c (20), K252c (21),4-bis(3-indolyl)-1H-pyrrole-2,5-dione (22),1H-indole-3-carboxylic acid (23), vanillic acid (24),4-hydroxybenzoic acid (25), 1-(2-phenyl)-1,2-ethandiol (26), 1-(2-furyl)-1,2-ethandiol (27) and 4-methoxy-3-methyl-2H-pyran-2-one (28), respectively. Among them, compound 1 and 2 were isolated from the natural sources for the first time. The other known compounds were identified as six indolecarbazole alkaloids (18-22), ten simple indole derivatives (2-10, 23), a isoflavonoid derived (11), a-naphthalene alkaloid (12),five benzene derivates (12-13,24-26) and four other kinds compounds (14-15,27-28). Besides, five N-acyl homoserine lactones (AHLs) signaling molecules of E.tarda were identified using gas chromatography-mass spectrometry (GC-MS) including C4-HSL, C6-oxo-HSL, C8-HSL, C8-oxo-HSL and C10-HSL.
Cytotoxic activities of these compounds against several cancer cell lines were assayed by MTT and SRB methods, and three compounds (2,16,18) showed appreciated cytotoxicity. The anti-bacterial activities of compounds 1-10,12 against Clostridium perfringens, Bacillus subtilis, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus and Candida albicans were tested by drug sensitive slips method and double dilution. The result indicated that compound 12 showed moderate inhibitions against C. perfringens and E. coli with MIC values of 31.25 and 37.5μg/mL, respectively.
In a word, two new natural indolealkaloids, two novel indolecarbazole alkaloids together with twenty-four known compounds were obtained from the two marine-derived microorganisms. 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.
经研究发现,多种海洋生物包括海绵、被囊动物、红藻以及海洋共附生微生物等都可以产生结构新颖的吲哚生物碱类化合物,该类化合物是海洋来源生物碱最重要的组成部分。这些海洋来源的吲哚类生物碱与陆生来源的相比不仅具有结构骨架的复杂性,而且存在卤素取代的现象。目前为止,海洋来源吲哚类生物碱具有细胞毒活性、抗病毒、抗微生物、抗炎、抑制拓扑异构酶Ⅰ等多种生物活性,因此该类化合物构效关系的研究广泛受到科学家们的关注。
将分离自青岛沿海及南海红树林样品的126株放线菌和细菌进行集成筛选。首先采用SRB法,以小鼠白血病P388肿瘤细胞为筛选模型进行体外抗肿瘤活性的筛选,然后结合HPLC指纹图谱及薄层色谱进行化学筛选,得到具有较强细胞毒活性的菌株4株,最终确定了1株主产吲哚咔唑生物碱、细胞毒活性较强的链霉菌Streptomyces sp. FMA作为进一步研究的目标菌株。同时,为了开发病原菌资源,选择了以吲哚生物碱为主要次生代谢产物并可产生多种高丝氨酸内酯(AHLs)信号分子的致病菌迟缓爱德华氏菌(E. tarda) LTB-4作为另一目标菌株。
以迟缓爱德华氏菌(E. tarda)和海洋链霉菌Streptomyces sp. FMA为研究对象,对发酵产物运用萃取,薄层层析,正相、反相硅胶柱层析,LH-20凝胶柱层析,反相高压液相等多种化学的分离纯化手段,进行活性次生代谢产物的追踪分离。从E. tarda LTB-4的次生代谢产物中分离得到15个单体化合物(1-15),从Streptomyces sp. FMA的次生代谢产物中分离得到13个单体化合物(16-28)。继而,利用理化性质和波谱学方法(IR,UV,MS,NMR等)结合化学反应的方法阐述了28个化合物的化学结构(化合物结构及名称参见Table 1),其中新天然产物2个(1,2),新化合物2个(16,17)。所得化合物的结构类型包括：吲哚咔唑类化合物(16-22)、简单吲哚类生物碱(1-10,23)、黄酮类(11)、苯类衍生物(12-13,24-26)、核苷碱基(14-15)、呋喃类(27)和不饱和内酯类(28)。由此可见,吲哚类生物碱是Streptomyces sp. FMA和E. tarda次生代谢产物的主要结构类型。
通过气相色谱和质谱连用(GC-MS)的测试手段,对迟缓爱德华氏菌(E. tarda)胞外的5种酰化高丝氨酸内酯(AHLs)信号分子进行了结构鉴定,分别为C4-HSL、C6-oxo-HSL、C8-HSL、C8-oxo-HSL和C10-HSL,为该类细菌信号传导的研究提供了依据。
利用SRB法、MTT法及药敏纸片法对分离获得的单体化合物的抗肿瘤、抗菌活性分别进行了初步评价。筛选出了3个抗肿瘤化合物(2、16、18)；1个抗菌活性化合物(12)。其中,化合物2对A549的IC50为6.24μM,化合物16对HL60和A549细胞的IC50分别为4.97μM和2.01μM化合物18对P388和Hela细胞的IC50分别为1.37μM和5.06μM；化合物12对产气杆菌(Clostridium perfringens)和大肠杆菌(E. coli)均有抑制作用,其最小抑菌浓度(MIC)分别为31.25μg/mL和37.5μg/mL。
综上,本文对两株海洋微生物的次生代谢产物进行了系统研究,共分离鉴定了28个化合物,包括天然来源的新吲哚生物碱2个,新吲哚咔唑类生物碱2个,较高抗肿瘤活性化合物3个；并且提供了1株能特征产生吲哚咔唑类生物碱的海洋链霉菌和1株可高产吲哚类生物碱的海洋细菌。这一研究丰富了海洋天然产物的结构类型,同时也为抗肿瘤药物的筛选提供了活性化合物及活性菌株。
Because of the special ecological environment, marine-derived microorganisms possess distinct and complex metabolic capabilities, resulting in wide diversity of their secondary metabolites in chemical structure and biological activity. Thus, bacterium and actinomycetes become important resources of active lead compounds. This thesis describes the bioactive constituents from marine-derived bacterium E. tarda and Streptomycetes sp. FMA. The work includes screening aimed strains, fermentation studies, bioassay-guided fractionation, structural elucidation, preliminary evaluation for anti-tumor and anti-bacterial activities of pure compounds.
A variety of marine sources including sponges, tunicates, red alga, acorn worms, and symbiotic bacteria have been shown to generate indole alkaloids, which represent the largest number and most complicated of the marine alkaloids (1/4 of total alkaloids). The alkaloids obtained from marine organisms frequently possess novel frameworks while in other cases terrestrially related compounds clearly exist. Marine metabolites often possess complexities such as halogen substituents. Their structure elucidation, chemical modification, stereochemistry, synthesis, and pharmacology have received a great deal of interdisciplinary attention from areas of research other than chemistry and include pharmacology, physiology, and medicine.
Four active strains were picked out based on integrated screening that combines the cytotoxicity against P388 cells with chemodiversity (HPLC and TLC properties) of the metabolites from 126 marine-derived actinomycetes and bacterias. Among them, Streptomycetes sp. FMA was selected for further study of their secondary metabolites exhibited high anti-tumor activities and a series of HPLC peaks with similar UV absorption to those of indolocarbazoles. Besides, the gram-negative bacterium E. tarda, pathogen of fish, animal and human was also found to display a series of HPLC peaks with similar UV absorption to those of indolalkaloids. In order to investigate the potential of pathogens for drug discovery, the secondary metabolites and AHLs of E. tarda were studied as well.
140L-scale fermentation of the E. tarda and 100L-scale fermentation of the Streptomycetes sp. FMA were performed to obtain the active extracts, respectively. By means of chromatography over silica gel column, Sephadex LH20, preparative TLC and semi-preparative HPLC, fifteen (1-15) and thirteen compounds (16-28) were isolated from E. tarda and Streptomycetes sp. FMA, respectively. Basing on their physico-chemical properties and spectral data (IR, UV, MS, NMR, etc.), twenty eight compounds were elucidated as 1,1-(3,3'-diindolyl)-2-phenylethane (1),3-(1H-indol-3-yl)-2,3'-bi-(1H-indole) (2),2,2-di(3-indolyl)-3-indolone (3), tri(1H-indol-3-yl) methane (4),2-[2,2-bis(1H-indol-3-yl)]ethylphenylamine (5), bis-(1H-indol-3-yl) phenylmethane (6),4-di(1H-indol-3-yl) methylphenol (7), (2S)-3,3-bis-(1H-indol-3-yl) propane-1,2-diol (8), Indole (9),2-(1H-indol-3-yl) ethanol (10), genistein (11), (2-Naphthyl)phenylamine (12), benzeneethanol (13), uracil (14), thymine (15), streptocarbazole A (16), streptocarbazole B (17),3'-(S)-epi-K252a (18),3'-(S)-K252a (19), RK 286c (20), K252c (21),4-bis(3-indolyl)-1H-pyrrole-2,5-dione (22),1H-indole-3-carboxylic acid (23), vanillic acid (24),4-hydroxybenzoic acid (25), 1-(2-phenyl)-1,2-ethandiol (26), 1-(2-furyl)-1,2-ethandiol (27) and 4-methoxy-3-methyl-2H-pyran-2-one (28), respectively. Among them, compound 1 and 2 were isolated from the natural sources for the first time. The other known compounds were identified as six indolecarbazole alkaloids (18-22), ten simple indole derivatives (2-10, 23), a isoflavonoid derived (11), a-naphthalene alkaloid (12),five benzene derivates (12-13,24-26) and four other kinds compounds (14-15,27-28). Besides, five N-acyl homoserine lactones (AHLs) signaling molecules of E.tarda were identified using gas chromatography-mass spectrometry (GC-MS) including C4-HSL, C6-oxo-HSL, C8-HSL, C8-oxo-HSL and C10-HSL.
Cytotoxic activities of these compounds against several cancer cell lines were assayed by MTT and SRB methods, and three compounds (2,16,18) showed appreciated cytotoxicity. The anti-bacterial activities of compounds 1-10,12 against Clostridium perfringens, Bacillus subtilis, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus and Candida albicans were tested by drug sensitive slips method and double dilution. The result indicated that compound 12 showed moderate inhibitions against C. perfringens and E. coli with MIC values of 31.25 and 37.5μg/mL, respectively.
In a word, two new natural indolealkaloids, two novel indolecarbazole alkaloids together with twenty-four known compounds were obtained from the two marine-derived microorganisms. 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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