细胞毒活性海洋真菌的筛选及其生物碱类代谢产物的研究
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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。为了寻找新的活性先导化合物,本论文采用了抗肿瘤活性筛选和现代化学分析相结合的方法,选取萨氏曲霉Aspergillus sydowi PFW1-13和Aspergillus sp. HSN-2作为目标菌株,对其活性次级代谢产物进行了系统研究。
采用海虾生物致死法和tsFT210细胞和K562细胞的流式细胞术筛选模型及抑菌试验筛选模型,以细胞周期抑制、细胞凋亡诱导以及坏死性细胞毒及抑菌圈为活性指标,结合化学筛选,从9个海洋样品(其中6个动物样品,三个漂浮物样品)中分离得到了287株微生物,其中具有强活性的菌株17株。
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分离手段,通过解析波谱数据并结合理化常数阐明了从萨氏曲霉Aspergillus sydowi PFW1-13中分得的35个化合物的结构:14-norpseurotin A (1), pseurotin A (4), 18-carbonyl tryprostatin A (5), methoxyl-spirotryprostatin B (6), 13-methoxyl verruculogen TR-2 (7), 12-hydroxyl terezines D (8), spirotryprostatin A (9), terezines D (10), fumitremorgin C (12), cyclotryprostatins B (13), verruculogen (16), tryptoquivaline O (18), fumiquinazolines F (19), fumiquinazoline G (20), fumiquinazoline J (21), fumiquinazoline A (22), fumiquinazoline C (23), fumiquinazoline D (24), bisdethiobis(methyl)gliotoxin (26), didehydrobisdethiobis- (methylthio)gliotoxin (27), fumigaclavine (29), fumigaclavine A (30),Pyripyropene A (31), Pyripyropene E (32), hydrohelvolic acid (33), helvolic acid (34),麦角甾醇(35),isosclerone (36),大黄素(37),大黄素-8-甲醚(38), Monomethylsulochrin (39), 5-methylbenzene-1,3-diol (40), 1,7-dihydroxyl-3-methyl-8-ketomethoxy- xanthone (41),苯甲酸(42), scytalone(43)(化合物结构及名称参见Fig. 1);从Aspergillus sp. HSN-2中分得的8个化合物的结构:呋喃螺内酰胺(2)和(3), tryprostatins B(11), 12, 13-dihydroxyfumitremorgin C (14), fumitremorgin B (15), cyclo-L-tryptophyl-L-proline (17), gliotoxin (25), 2,5-Piperazinedione (28) (化合物结构及名称参见Fig. 2)。生物碱1、5-8和降达玛烷型三萜类化合物33为新化合物。
利用流式细胞术结合形态学检测、MTT和SRB法,对所分得的单体化合物的体外抗肿瘤活性进行了初步评价。结果表明,新化合物1对K562细胞有弱的增殖抑制活性;新化合物5、6对多种人癌细胞及哺乳动物癌细胞具有中等强度的细胞增殖抑制活性;新化合物7、8及33对多种人癌细胞及哺乳动物癌细胞有一定程度的细胞增殖抑制活性;化合物41对K562细胞具有一定的凋亡诱导作用;化合物32对K562和P388细胞有中等强度的增殖抑制活性;化合物2、16、18-24、29、36及38具有一定程度的细胞增殖抑制活性;化合物10-13、15、26、27、29和31对tsFT210细胞具有一定程度的细胞增殖抑制活性;化合物35有诱导凋亡和细胞毒活性。在抑菌试验中,化合物1、4、33和34对对大肠杆菌(Eschetichia coli)、将枯草芽孢杆菌(Bacillus subtilis)、溶壁微球菌(Micrococcus lysoleikticus)显示不同程度的抑菌活性。
综上,本文采用组合筛选的方法获得海洋活性菌株,并阐明了2株海洋活性菌株代谢产物中43个化合物的结构,其中生物碱类化合物32个,新的生物碱类化合物5个,证明本方法是寻找结构新颖的先导化合物的有效手段。上述研究为抗肿瘤药物的研究提供了新化合物,并为从海洋微生物中分离有活性的生物碱类化合物的研究提供了基础资料。
Marine microorganism is a rich source of secondary metabolites content with diverse structures and various biological activities. A study is carried out to investigate the bioactive lead compounds derived from marine microorganisms. By combinatory use of brine shrimp bioassay testing, cytometric bioassay against tsFT210 cell line and K562 cell line and antibiotic experiment, and chemical analysis, 17 bioactive strains have been screened from 287 strains isolated from nine marine samples. Two fungal strains Aspergillus sydowi PFW1-13 and Aspergillus sp. HSN-2 are selected for further chemical investigation.
Monitoring by bioassay-guided isolation, the active fraction is chromatographed on silica gel, Sephadex LH-20 and prepared TLC, and preparative reversed phase HPLC, respectively, thirty five compounds are isolated from the marine-derived fungal strain Aspergillus sydowi PFW1-13. By means of spectroscopic methods (1D-NMR, 2D-NMR, MS, IR, UV, etc.), their structures are elucidated as 14-norpseurotin A (1), pseurotin A (4), 18-carbonyl tryprostatin A (5), methoxyl-spirotryprostatin B (6), 13-methoxyl verruculogen TR-2 (7), 12-hydroxyl terezines D (8), spirotryprostatin A (9), terezines D (10), fumitremorgin C (12), cyclotryprostatins B (13), verruculogen (16), tryptoquivaline O (18), fumiquinazolines F (19), fumiquinazoline G (20), fumiquinazoline J (21), fumiquinazoline A (22), fumiquinazoline C (23), fumiquinazoline D (24), bisdethiobis(methyl)gliotoxin (26), didehydrobisdethiobis- (methylthio)gliotoxin (27), fumigaclavine (29), fumigaclavine A (30), Pyripyropene A (31), Pyripyropene E (32), hydrohelvolic acid (33), helvolic acid (34), Ergosterol (35), isosclerone (36), emodin(37), questin (38), Monomethylsulochrin (39), 5-methyl- benzene-1,3-diol (40), 1,7-dihydroxyl-3-methyl-8-ketomethoxyxanthone (41), benzoic Acid (42), scytalone (43). By the same procedure, eight compounds are isolated from the fungal strain Aspergillus sp. HSN-2. The structures are elucidated as furanylspiro-lactam (2) and (3), typrostatins B(11), 12, 13-dihydroxyfumitremorgin C (14), fumitremorgin B (15), cyclo-L-tryptophyl-L-proline (17), gliotoxin (25), 2,5- Piperazinedione (28). Among them, compounds 1, 5-8 and 33 are new compounds.
The anti-tumor activities of these compounds are evaluated in vitro by SRB and flowed cytometry using mouse cdc2 mutant cells tsFT210, mouse leukemia cells P388, human leukemia carcinoma cells K562 and human cancer cells A549, BEL-7402 and HL60. Thirty compounds show potential anti-tumor activities. New compounds 1, 5, 6 and 33 exhibit moderate inhibiting the proliferation of many cancer cells, such as mouse leukemia cells P388, human cancer cells A549, BEL-7402 and HL60. New compounds 7, 8 and 33 inhibit the proliferation of mouse leukemia cells P388, human cancer cells A549, BEL-7402 and HL60. Compound 41 has apoptosis activity. Compound 32 exhibit moderate inhibiting the proliferation of K562 and P388 cell lines. Compounds 2, 16, 18-24, 29, 36 and 38 inhibit the proliferation of tsFT210 cells. Compounds 10-13, 15, 26, 27, 29 and 31 show weak inhibiting the proliferation of tsFT210 cells. Compound 35 exhibits apoptosis inducing and cytotoxic activities. In addition, compounds 1, 4, 33 and 34 are found to be active against Escherichia coli, Bacillus subtilis and Micrococcus lysoleikticus.
In a word, there are forty three compounds which are obtained from the two fungal strains, five compounds in thirty two alkaloid compounds are new compounds. Studies mentioned above provide novel structures for searching leading antitumor compounds and it proves the method we use is effective in finding new active alkaloid compounds.
采用海虾生物致死法和tsFT210细胞和K562细胞的流式细胞术筛选模型及抑菌试验筛选模型,以细胞周期抑制、细胞凋亡诱导以及坏死性细胞毒及抑菌圈为活性指标,结合化学筛选,从9个海洋样品(其中6个动物样品,三个漂浮物样品)中分离得到了287株微生物,其中具有强活性的菌株17株。
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分离手段,通过解析波谱数据并结合理化常数阐明了从萨氏曲霉Aspergillus sydowi PFW1-13中分得的35个化合物的结构:14-norpseurotin A (1), pseurotin A (4), 18-carbonyl tryprostatin A (5), methoxyl-spirotryprostatin B (6), 13-methoxyl verruculogen TR-2 (7), 12-hydroxyl terezines D (8), spirotryprostatin A (9), terezines D (10), fumitremorgin C (12), cyclotryprostatins B (13), verruculogen (16), tryptoquivaline O (18), fumiquinazolines F (19), fumiquinazoline G (20), fumiquinazoline J (21), fumiquinazoline A (22), fumiquinazoline C (23), fumiquinazoline D (24), bisdethiobis(methyl)gliotoxin (26), didehydrobisdethiobis- (methylthio)gliotoxin (27), fumigaclavine (29), fumigaclavine A (30),Pyripyropene A (31), Pyripyropene E (32), hydrohelvolic acid (33), helvolic acid (34),麦角甾醇(35),isosclerone (36),大黄素(37),大黄素-8-甲醚(38), Monomethylsulochrin (39), 5-methylbenzene-1,3-diol (40), 1,7-dihydroxyl-3-methyl-8-ketomethoxy- xanthone (41),苯甲酸(42), scytalone(43)(化合物结构及名称参见Fig. 1);从Aspergillus sp. HSN-2中分得的8个化合物的结构:呋喃螺内酰胺(2)和(3), tryprostatins B(11), 12, 13-dihydroxyfumitremorgin C (14), fumitremorgin B (15), cyclo-L-tryptophyl-L-proline (17), gliotoxin (25), 2,5-Piperazinedione (28) (化合物结构及名称参见Fig. 2)。生物碱1、5-8和降达玛烷型三萜类化合物33为新化合物。
利用流式细胞术结合形态学检测、MTT和SRB法,对所分得的单体化合物的体外抗肿瘤活性进行了初步评价。结果表明,新化合物1对K562细胞有弱的增殖抑制活性;新化合物5、6对多种人癌细胞及哺乳动物癌细胞具有中等强度的细胞增殖抑制活性;新化合物7、8及33对多种人癌细胞及哺乳动物癌细胞有一定程度的细胞增殖抑制活性;化合物41对K562细胞具有一定的凋亡诱导作用;化合物32对K562和P388细胞有中等强度的增殖抑制活性;化合物2、16、18-24、29、36及38具有一定程度的细胞增殖抑制活性;化合物10-13、15、26、27、29和31对tsFT210细胞具有一定程度的细胞增殖抑制活性;化合物35有诱导凋亡和细胞毒活性。在抑菌试验中,化合物1、4、33和34对对大肠杆菌(Eschetichia coli)、将枯草芽孢杆菌(Bacillus subtilis)、溶壁微球菌(Micrococcus lysoleikticus)显示不同程度的抑菌活性。
综上,本文采用组合筛选的方法获得海洋活性菌株,并阐明了2株海洋活性菌株代谢产物中43个化合物的结构,其中生物碱类化合物32个,新的生物碱类化合物5个,证明本方法是寻找结构新颖的先导化合物的有效手段。上述研究为抗肿瘤药物的研究提供了新化合物,并为从海洋微生物中分离有活性的生物碱类化合物的研究提供了基础资料。
Marine microorganism is a rich source of secondary metabolites content with diverse structures and various biological activities. A study is carried out to investigate the bioactive lead compounds derived from marine microorganisms. By combinatory use of brine shrimp bioassay testing, cytometric bioassay against tsFT210 cell line and K562 cell line and antibiotic experiment, and chemical analysis, 17 bioactive strains have been screened from 287 strains isolated from nine marine samples. Two fungal strains Aspergillus sydowi PFW1-13 and Aspergillus sp. HSN-2 are selected for further chemical investigation.
Monitoring by bioassay-guided isolation, the active fraction is chromatographed on silica gel, Sephadex LH-20 and prepared TLC, and preparative reversed phase HPLC, respectively, thirty five compounds are isolated from the marine-derived fungal strain Aspergillus sydowi PFW1-13. By means of spectroscopic methods (1D-NMR, 2D-NMR, MS, IR, UV, etc.), their structures are elucidated as 14-norpseurotin A (1), pseurotin A (4), 18-carbonyl tryprostatin A (5), methoxyl-spirotryprostatin B (6), 13-methoxyl verruculogen TR-2 (7), 12-hydroxyl terezines D (8), spirotryprostatin A (9), terezines D (10), fumitremorgin C (12), cyclotryprostatins B (13), verruculogen (16), tryptoquivaline O (18), fumiquinazolines F (19), fumiquinazoline G (20), fumiquinazoline J (21), fumiquinazoline A (22), fumiquinazoline C (23), fumiquinazoline D (24), bisdethiobis(methyl)gliotoxin (26), didehydrobisdethiobis- (methylthio)gliotoxin (27), fumigaclavine (29), fumigaclavine A (30), Pyripyropene A (31), Pyripyropene E (32), hydrohelvolic acid (33), helvolic acid (34), Ergosterol (35), isosclerone (36), emodin(37), questin (38), Monomethylsulochrin (39), 5-methyl- benzene-1,3-diol (40), 1,7-dihydroxyl-3-methyl-8-ketomethoxyxanthone (41), benzoic Acid (42), scytalone (43). By the same procedure, eight compounds are isolated from the fungal strain Aspergillus sp. HSN-2. The structures are elucidated as furanylspiro-lactam (2) and (3), typrostatins B(11), 12, 13-dihydroxyfumitremorgin C (14), fumitremorgin B (15), cyclo-L-tryptophyl-L-proline (17), gliotoxin (25), 2,5- Piperazinedione (28). Among them, compounds 1, 5-8 and 33 are new compounds.
The anti-tumor activities of these compounds are evaluated in vitro by SRB and flowed cytometry using mouse cdc2 mutant cells tsFT210, mouse leukemia cells P388, human leukemia carcinoma cells K562 and human cancer cells A549, BEL-7402 and HL60. Thirty compounds show potential anti-tumor activities. New compounds 1, 5, 6 and 33 exhibit moderate inhibiting the proliferation of many cancer cells, such as mouse leukemia cells P388, human cancer cells A549, BEL-7402 and HL60. New compounds 7, 8 and 33 inhibit the proliferation of mouse leukemia cells P388, human cancer cells A549, BEL-7402 and HL60. Compound 41 has apoptosis activity. Compound 32 exhibit moderate inhibiting the proliferation of K562 and P388 cell lines. Compounds 2, 16, 18-24, 29, 36 and 38 inhibit the proliferation of tsFT210 cells. Compounds 10-13, 15, 26, 27, 29 and 31 show weak inhibiting the proliferation of tsFT210 cells. Compound 35 exhibits apoptosis inducing and cytotoxic activities. In addition, compounds 1, 4, 33 and 34 are found to be active against Escherichia coli, Bacillus subtilis and Micrococcus lysoleikticus.
In a word, there are forty three compounds which are obtained from the two fungal strains, five compounds in thirty two alkaloid compounds are new compounds. Studies mentioned above provide novel structures for searching leading antitumor compounds and it proves the method we use is effective in finding new active alkaloid compounds.
引文
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