海洋微生物代谢产物抗肿瘤活性成分研究
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摘要
海洋微生物生存环境特殊,其次级代谢产物化学结构新颖、种类繁多,是新活性先导化合物的重要来源。为了寻找抗肿瘤活性先导化合物,本论文采用活性追踪的方法开展了海洋微生物抗肿瘤活性代谢产物的研究工作。内容包括:海洋微生物抗肿瘤活性菌株的分级组合筛选;活性菌株复筛和发酵条件考察;抗肿瘤活性成分的追踪分离;化合物单体的结构解析;单体化合物抗肿瘤活性的初步评价。
采用海虾生物致死法和tsFT210细胞的流式细胞术筛选模型,以细胞周期抑制和细胞凋亡诱导以及坏死性细胞毒为活性指标,对采自青岛近海由实验室分离保藏的164株海洋微生物,进行了抗肿瘤活性的分级组合筛选。经海虾生物致死法一级初筛,得到活性菌株60株(LC_(50)<500μg/mL),阳性率为36.6%。对初筛有效的60株菌利用流式细胞术筛选模型进行二级复筛,得到具有抗肿瘤活性的菌株27株,阳性率为复筛菌株数的45.0%、初筛菌株总数的16.5%。
本论文选择3株代谢产物活性强、稳定性好的放线菌H1002和007株,以及真菌H1-04作为目标菌株,对其活性产物进行了研究。通过培养基选择试验,发酵时间试验,确定了3株目标菌的大量发酵条件。经大量发酵和萃取实验分别得到了3株目标菌的活性部位,反复运用薄层层析,正相、反相硅胶柱层析,LH-20凝胶柱层析,反相高压液相等化学的分离纯化手段,采用小鼠乳腺癌tsFT210细胞的镜检结合流式细胞术的活性追踪模型,通过活性成分的跟踪分离,从H1002的代谢产物中分离得到12个化合物单体(1-12);从007中得到了6个单体化合物(4、7、8、13-15);从H1-04中分离得到12个单体化合物(16-27)。
继而,通过解析波谱数据并结合理化常数阐明了26个化合物的化学结构(化合物结构及名称参见Table 1),其中生物碱类化合物9个(吲哚咔唑类生物碱化合物2个,喹唑啉生物碱类化合物6个,其他生物碱类化合物1
Marine microorganisms continue to be an important source of bioactive secondary metabolites. A study was carried out to investigate the potential anti-tumor compounds derived from marine microorganisms. This dissertation describes the discovery of several antitumor lead compounds produced by marine microorganisms. Studies include screening of microbial strains, selecting aimed strains, fermentation studies, bioassay-guided fractionation, structural elucidation and preliminary evaluation for anti-tumor activities of pure compounds.This dissertation is organized in six chapters. Chapter One is an introduction and overview of the current studies in the field. The discovery of antitumor compounds produced by marine microorganisms, actinomycetes and fungi, are reviewed in Chapter One. In Chapter Two, the results from a study of gradated-combinatorial screening for the antitumor-active microbial strains is presented. The study was carried out by the gradated combination of a 96-well plate lethality bioassay using brine shrimp and a flow cytometric bioassay using mouse tsFT210 cells. [At the first step, the 164 strains of marine-derived microbes, isolated from the marine samples collected at the near shore alone the Qingdao's coast line and around Jiaozhou Bay, were first screened by Brine Shrimp Lethality assay to obtain 60 strains which showed lethiferous activity on brine shrimp, and possessed 36.6% of total 164 strains tested. For the second step, the 60 strains were subjected to the flow cytometric second screening using mouse tsFT210 cells and total 27 strains were found to have antitumor activities on the tsFT210 cells, which possessed 45.0% of the 60 strains and 16.5% of total 164 strains, respectively. J is Chapter Three describes the results of third screening (stability-tests for the bioactive components) and fermentation studies performed on the aimed strains.
The metabolites of 3 strains including 2 actinomycete (HI002 and 007) and 1 fungal (HI-04) strains showed better stability in stability-tests. Therefore, these three well tested strains were chosen as the aimed strains to investigate their bioactive metabolites in this study. The time course experiments for the fermentation of these three producing strains were then carried out, followed by solvent extraction tests for the active components. Then, large-scale fermentation and preparation of the active fractions were performed to obtain the active fractions of the three strains. The two aimed strains, 007 and HI-04, were identified as Actinomadura sp. nov. and Aspergillus fumigatus Fres., respectively, through taxonomic studies.Chapter Four describes the results of bioassay-guided separation of the metabolites of the three aimed strains. Twelve compounds (1-12) were obtained from the metabolites of actinomycete HI002, six compounds (4, 7, 8 and 13-15) from Actinomadura sp. nov. 007, and twelve compounds (16-27) from Aspergillus fumigatus Fres. HI-04, respectively.Chapter Five describes the structural elucidation of the isolated compounds. The chemical structures of 1-27 (as shown as in Table 1) were investigated on the basis of their physical and-chemical properties and especially by the using modern spectroscopic methods. The structure of one new compound (13) has been confirmed, and identification of the other compounds including one new natural compound (27).Chapter Six describes the results of preliminary evaluation for antitumor activities of the pure compounds. The bioassay methods include flow cytometry, SRB and MTT methods. Bioassay results indicated: compound 13 inhibited the proliferation of human cancer A549, BEL-7402 and HL60 cells and mouse leukemia P388 cells with the inhibition rates of 82.6%, 57.3%, 76.1% and 62.2%, assay by SRB (A549 and BEL-7402) or MTT (HL60 and P388) method at 1 j*M, respectively. It also inhibited the proliferation of mouse cancer tsFT210 cells with the inhibition rates of 28.3% at 21 //M and 20.5% at 2.1 //M in the SRB
assay. Flow cytometric analysis indicated that 13 inhibited the cell cycle of tsFT210 cells mainly at the G2/M phase. Compound 16 had apoptosis inducing or cytotoxic activities at the lower concentrations. Compounds 14 and 17-27 could inhibit the proliferation of tsFT210 cells. Compound 2 could arrest the cell cycle of tsFT210 cells at G0/G1 phase. Compound 11 could arrest the cell cycle of tsFT210 cells at G2/M phase.
采用海虾生物致死法和tsFT210细胞的流式细胞术筛选模型,以细胞周期抑制和细胞凋亡诱导以及坏死性细胞毒为活性指标,对采自青岛近海由实验室分离保藏的164株海洋微生物,进行了抗肿瘤活性的分级组合筛选。经海虾生物致死法一级初筛,得到活性菌株60株(LC_(50)<500μg/mL),阳性率为36.6%。对初筛有效的60株菌利用流式细胞术筛选模型进行二级复筛,得到具有抗肿瘤活性的菌株27株,阳性率为复筛菌株数的45.0%、初筛菌株总数的16.5%。
本论文选择3株代谢产物活性强、稳定性好的放线菌H1002和007株,以及真菌H1-04作为目标菌株,对其活性产物进行了研究。通过培养基选择试验,发酵时间试验,确定了3株目标菌的大量发酵条件。经大量发酵和萃取实验分别得到了3株目标菌的活性部位,反复运用薄层层析,正相、反相硅胶柱层析,LH-20凝胶柱层析,反相高压液相等化学的分离纯化手段,采用小鼠乳腺癌tsFT210细胞的镜检结合流式细胞术的活性追踪模型,通过活性成分的跟踪分离,从H1002的代谢产物中分离得到12个化合物单体(1-12);从007中得到了6个单体化合物(4、7、8、13-15);从H1-04中分离得到12个单体化合物(16-27)。
继而,通过解析波谱数据并结合理化常数阐明了26个化合物的化学结构(化合物结构及名称参见Table 1),其中生物碱类化合物9个(吲哚咔唑类生物碱化合物2个,喹唑啉生物碱类化合物6个,其他生物碱类化合物1
Marine microorganisms continue to be an important source of bioactive secondary metabolites. A study was carried out to investigate the potential anti-tumor compounds derived from marine microorganisms. This dissertation describes the discovery of several antitumor lead compounds produced by marine microorganisms. Studies include screening of microbial strains, selecting aimed strains, fermentation studies, bioassay-guided fractionation, structural elucidation and preliminary evaluation for anti-tumor activities of pure compounds.This dissertation is organized in six chapters. Chapter One is an introduction and overview of the current studies in the field. The discovery of antitumor compounds produced by marine microorganisms, actinomycetes and fungi, are reviewed in Chapter One. In Chapter Two, the results from a study of gradated-combinatorial screening for the antitumor-active microbial strains is presented. The study was carried out by the gradated combination of a 96-well plate lethality bioassay using brine shrimp and a flow cytometric bioassay using mouse tsFT210 cells. [At the first step, the 164 strains of marine-derived microbes, isolated from the marine samples collected at the near shore alone the Qingdao's coast line and around Jiaozhou Bay, were first screened by Brine Shrimp Lethality assay to obtain 60 strains which showed lethiferous activity on brine shrimp, and possessed 36.6% of total 164 strains tested. For the second step, the 60 strains were subjected to the flow cytometric second screening using mouse tsFT210 cells and total 27 strains were found to have antitumor activities on the tsFT210 cells, which possessed 45.0% of the 60 strains and 16.5% of total 164 strains, respectively. J is Chapter Three describes the results of third screening (stability-tests for the bioactive components) and fermentation studies performed on the aimed strains.
The metabolites of 3 strains including 2 actinomycete (HI002 and 007) and 1 fungal (HI-04) strains showed better stability in stability-tests. Therefore, these three well tested strains were chosen as the aimed strains to investigate their bioactive metabolites in this study. The time course experiments for the fermentation of these three producing strains were then carried out, followed by solvent extraction tests for the active components. Then, large-scale fermentation and preparation of the active fractions were performed to obtain the active fractions of the three strains. The two aimed strains, 007 and HI-04, were identified as Actinomadura sp. nov. and Aspergillus fumigatus Fres., respectively, through taxonomic studies.Chapter Four describes the results of bioassay-guided separation of the metabolites of the three aimed strains. Twelve compounds (1-12) were obtained from the metabolites of actinomycete HI002, six compounds (4, 7, 8 and 13-15) from Actinomadura sp. nov. 007, and twelve compounds (16-27) from Aspergillus fumigatus Fres. HI-04, respectively.Chapter Five describes the structural elucidation of the isolated compounds. The chemical structures of 1-27 (as shown as in Table 1) were investigated on the basis of their physical and-chemical properties and especially by the using modern spectroscopic methods. The structure of one new compound (13) has been confirmed, and identification of the other compounds including one new natural compound (27).Chapter Six describes the results of preliminary evaluation for antitumor activities of the pure compounds. The bioassay methods include flow cytometry, SRB and MTT methods. Bioassay results indicated: compound 13 inhibited the proliferation of human cancer A549, BEL-7402 and HL60 cells and mouse leukemia P388 cells with the inhibition rates of 82.6%, 57.3%, 76.1% and 62.2%, assay by SRB (A549 and BEL-7402) or MTT (HL60 and P388) method at 1 j*M, respectively. It also inhibited the proliferation of mouse cancer tsFT210 cells with the inhibition rates of 28.3% at 21 //M and 20.5% at 2.1 //M in the SRB
assay. Flow cytometric analysis indicated that 13 inhibited the cell cycle of tsFT210 cells mainly at the G2/M phase. Compound 16 had apoptosis inducing or cytotoxic activities at the lower concentrations. Compounds 14 and 17-27 could inhibit the proliferation of tsFT210 cells. Compound 2 could arrest the cell cycle of tsFT210 cells at G0/G1 phase. Compound 11 could arrest the cell cycle of tsFT210 cells at G2/M phase.
引文
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