海洋真菌中新型抗肿瘤活性物质的研究
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摘要
自从1967年在美国生物工程学会上提出“向海洋要药”的口号以来,从海洋生物中分离到了许多结构新颖、活性独特的化合物。然而,随着海洋微生物代谢产物研究的进行,很多研究者认为原本从海洋动植物中分离到的生物活性物质的真正来源是与海洋生物共附生的海洋微生物,因此海洋微生物代谢产物的研究逐渐成为海洋天然产物研究领域的热点。有效的生物活性筛选模型能够提高寻找活性天然产物的效率。稻瘟霉生物活性筛选模型是以观察稻瘟霉分生孢子和菌丝的形态变化为指标的,在该模型指导下已经分离得到了一系列具有抗肿瘤、抗真菌作用的化合物,如rhizoxin,fusarielin A,phomopsidin等。
本文以海洋真菌为研究对象,以寻找具有抗肿瘤或者抗真菌作用的化合物为目标。在稻瘟霉生物活性模型的指导下,对从1012株海洋真菌中选取的10株活性真菌的发酵培养液进行了系统的化学研究,从中分离得到了40个化合物,利用波谱分析等手段鉴定了其中32个。它们分别是:paxilline(1),paspaline(2),emeniveol(3),12-demethylpaspaline-11-ene(4),13-desoxypaxilline(5),emindole SB(6),paspaline B(7),β-PC-M6(8),pyrenocine A(9),pyrenocine C(10),pyrenocine E(11),zearalenone(12),8'-hydroxyzearalenone(13),5'-hydroxyzearalenol(14),zearalenol(15),5'-hydroxyzearalenone(16),7'-dehydrozearalenone(17),fusarielin A(18),fusarielin B(19),fusarielin C(20),fusarielin E(21),5-(acetyloxy)-1,5-dihydro-2H-pyrrol-2-one(22),fusapyrone(23),deoxyfusapyrone(24),asteltoxin(25),cycloechinulin(26),penicillic acid(27),4-hydroxymellein(28),α,β-dehydrocurvularin(29),terrein(30),ascochlorin(31),mycophenolic acid(32)。其中化合物4,14,16,21为新化合物,化合物22为首次自天然物中分离得到,化合物3为首次从青霉属真菌中分离得到,并首次测定了化合物5和14的X-射线单晶衍射结构。化合物1-8的获得为重要的神经毒素paxilline(1)可能的生物合成途径提供了更多的化学证据,并在此基础上对已有的生物合成路线进行了补充和修正。
对稻瘟霉模型的活性试验表明,化合物18能够引起稻瘟霉P-2b菌株的分生孢子和菌丝发生强烈的卷曲变形,对菌丝生长的最小抑制浓度为12.5μg/mL;化合物1,2,6,21,23-24对稻瘟霉P-2b菌株具有弱卷曲变形活性,对菌丝生长的最小抑制浓度分别为1.6,3.1,3.1,50,12.5和1.6μg/mL;化合物3-5,7,9,11-13,16-17,20,22,25,27-32对稻瘟霉P-2b菌株仅有抑制活性,对菌丝生长的最小抑制浓度在0.31-400μg/mL;其余化合物对稻瘟霉P-2b菌株无明显活性。对PC12细胞活性测试显示,化合物9-11,18-19和21在浓度为1-20μg/mL时具有诱导PC12细胞分化的活性;在浓度为5-20μg/mL时,化合物1-8和20对PC12细胞具有毒性。
利用稻瘟霉模型跟踪分离得到的化合物与文献报道的抗真菌或细胞毒活性结果具有良好的一致性,证明该活性模型能够有效指导海洋真菌生物活性物质的分离。
Thousands of new compounds have been isolated from marine organisms since the symposium entitled 'Drugs from the sea' in 1967.Most of them are structurally unique and show significant biological activity.Many researchers believe that these bioactive compounds are actually produced by 'symbiotic' microorganisms.Therefore,chemical studies of marine microorganisms have been a hotspot in the area of marine natural products in the past several years.Effective bioassay systems are important in searching for new bioactive natural products.Pyricularia oryzae model is such a screening method that depends on detecting deformation of mycelia germinated from conidia of P.oryzae P-2b. Kinds of antimitotic and antifungal compounds,such as rhizoxin,fusarielin A and phomopsidin,were found using this screening system.
In order to search for new antimitotic and antifungal substances from marine-derived fungi,we apply this method as a primarily screening system and guided the purification process.During the systemmetric chemical research on the 10 bioactive fungus out of 1012 tested one,we obtained forty metabolites and thirty two of them were identified as paxilline(1),paspaline(2),emeniveol(3),12-demethylpaspaline-11-ene(4), 13-desoxypaxilline(5),emindole SB(6),paspaline B(7),β-PC-M6(8),pyrenocine A(9), pyrenocine C(10),pyrenocine E(11),zearalenone(12),8'-hydroxyzearalenone(13), 5'-hydroxyzearalenol(14),zearalenol(15),5'-hydroxyzearalenone(16),7'-dehydrozearalenone (17),fusarielin A(18),fusarielin B(19),fusarielin C(20),fusarielin E(21), 5-(acetyloxy)-1,5-dihydro-2H-pyrrol-2-one(22),fusapyrone(23),deoxyfusapyrone(24), asteltoxin(25),cycloechinulin(26),penicillic acid(27),4-hydroxymellein(28),α,β-dehydrocurvularin(29),terrein(30),ascochlorin(31) and mycophenolic acid(32), respectively.Coumpounds 4,14,16,and 21 are new compounds,and the single crystal X-ray diffraction analysis of 13-desoxypaxilline(5) and 5'-hydroxyzearalenol(14) was obtained firstly.It is the first isolation of emeniveol(3) from the genus Penicillium,and 5-(acetyloxy)-1,5-dihydro-2H-pyrrol-2-one(22) from natural source.We thus provided more evidence of the proposed biosynthetic pathway of the neurotoxin paxilline(1),and made some modifications to the proposed biosynthesis scheme based on chemical identification of those related metabolites 1-8.
Activity experiments showed that compound 18 induced significant morphalogical abnormality of the conidia and mycelia of P.oryzae P-2b by curling effect,and inhibited the growth of them with minimum inhibition concentration(MIC) of 12.5μg/mL;compounds 1, 2,6,21,and 23-24 caused weak curling deformation,with MIC of 1.6,3.1,3.1,50,12.5 and 1.6μg/mL,respectively;compounds 3-5,7,9,11-13,16-17,20,22,25,and 27-32 showed no deformation effect,and the MIC values were between 0.31-400μg/mL;other compounds showed little effect against P.oryzae P-2b.Compounds 9-11,18-19,and 21 were shown to induce neuronal differentiation in rat PC12 cells,while compounds 1-8 and 20 showed cytotoxic activity against rat PC12 cells.
The bioactivity of those compounds against P.oryzae P-2b in our study was in accordance with the antifungal or cytotoxic effects reported by other researchers,thus the P. oryzae model was proved to be efficient in guiding the seperation of bioactive metabolites from marine-derived fungi.
本文以海洋真菌为研究对象,以寻找具有抗肿瘤或者抗真菌作用的化合物为目标。在稻瘟霉生物活性模型的指导下,对从1012株海洋真菌中选取的10株活性真菌的发酵培养液进行了系统的化学研究,从中分离得到了40个化合物,利用波谱分析等手段鉴定了其中32个。它们分别是:paxilline(1),paspaline(2),emeniveol(3),12-demethylpaspaline-11-ene(4),13-desoxypaxilline(5),emindole SB(6),paspaline B(7),β-PC-M6(8),pyrenocine A(9),pyrenocine C(10),pyrenocine E(11),zearalenone(12),8'-hydroxyzearalenone(13),5'-hydroxyzearalenol(14),zearalenol(15),5'-hydroxyzearalenone(16),7'-dehydrozearalenone(17),fusarielin A(18),fusarielin B(19),fusarielin C(20),fusarielin E(21),5-(acetyloxy)-1,5-dihydro-2H-pyrrol-2-one(22),fusapyrone(23),deoxyfusapyrone(24),asteltoxin(25),cycloechinulin(26),penicillic acid(27),4-hydroxymellein(28),α,β-dehydrocurvularin(29),terrein(30),ascochlorin(31),mycophenolic acid(32)。其中化合物4,14,16,21为新化合物,化合物22为首次自天然物中分离得到,化合物3为首次从青霉属真菌中分离得到,并首次测定了化合物5和14的X-射线单晶衍射结构。化合物1-8的获得为重要的神经毒素paxilline(1)可能的生物合成途径提供了更多的化学证据,并在此基础上对已有的生物合成路线进行了补充和修正。
对稻瘟霉模型的活性试验表明,化合物18能够引起稻瘟霉P-2b菌株的分生孢子和菌丝发生强烈的卷曲变形,对菌丝生长的最小抑制浓度为12.5μg/mL;化合物1,2,6,21,23-24对稻瘟霉P-2b菌株具有弱卷曲变形活性,对菌丝生长的最小抑制浓度分别为1.6,3.1,3.1,50,12.5和1.6μg/mL;化合物3-5,7,9,11-13,16-17,20,22,25,27-32对稻瘟霉P-2b菌株仅有抑制活性,对菌丝生长的最小抑制浓度在0.31-400μg/mL;其余化合物对稻瘟霉P-2b菌株无明显活性。对PC12细胞活性测试显示,化合物9-11,18-19和21在浓度为1-20μg/mL时具有诱导PC12细胞分化的活性;在浓度为5-20μg/mL时,化合物1-8和20对PC12细胞具有毒性。
利用稻瘟霉模型跟踪分离得到的化合物与文献报道的抗真菌或细胞毒活性结果具有良好的一致性,证明该活性模型能够有效指导海洋真菌生物活性物质的分离。
Thousands of new compounds have been isolated from marine organisms since the symposium entitled 'Drugs from the sea' in 1967.Most of them are structurally unique and show significant biological activity.Many researchers believe that these bioactive compounds are actually produced by 'symbiotic' microorganisms.Therefore,chemical studies of marine microorganisms have been a hotspot in the area of marine natural products in the past several years.Effective bioassay systems are important in searching for new bioactive natural products.Pyricularia oryzae model is such a screening method that depends on detecting deformation of mycelia germinated from conidia of P.oryzae P-2b. Kinds of antimitotic and antifungal compounds,such as rhizoxin,fusarielin A and phomopsidin,were found using this screening system.
In order to search for new antimitotic and antifungal substances from marine-derived fungi,we apply this method as a primarily screening system and guided the purification process.During the systemmetric chemical research on the 10 bioactive fungus out of 1012 tested one,we obtained forty metabolites and thirty two of them were identified as paxilline(1),paspaline(2),emeniveol(3),12-demethylpaspaline-11-ene(4), 13-desoxypaxilline(5),emindole SB(6),paspaline B(7),β-PC-M6(8),pyrenocine A(9), pyrenocine C(10),pyrenocine E(11),zearalenone(12),8'-hydroxyzearalenone(13), 5'-hydroxyzearalenol(14),zearalenol(15),5'-hydroxyzearalenone(16),7'-dehydrozearalenone (17),fusarielin A(18),fusarielin B(19),fusarielin C(20),fusarielin E(21), 5-(acetyloxy)-1,5-dihydro-2H-pyrrol-2-one(22),fusapyrone(23),deoxyfusapyrone(24), asteltoxin(25),cycloechinulin(26),penicillic acid(27),4-hydroxymellein(28),α,β-dehydrocurvularin(29),terrein(30),ascochlorin(31) and mycophenolic acid(32), respectively.Coumpounds 4,14,16,and 21 are new compounds,and the single crystal X-ray diffraction analysis of 13-desoxypaxilline(5) and 5'-hydroxyzearalenol(14) was obtained firstly.It is the first isolation of emeniveol(3) from the genus Penicillium,and 5-(acetyloxy)-1,5-dihydro-2H-pyrrol-2-one(22) from natural source.We thus provided more evidence of the proposed biosynthetic pathway of the neurotoxin paxilline(1),and made some modifications to the proposed biosynthesis scheme based on chemical identification of those related metabolites 1-8.
Activity experiments showed that compound 18 induced significant morphalogical abnormality of the conidia and mycelia of P.oryzae P-2b by curling effect,and inhibited the growth of them with minimum inhibition concentration(MIC) of 12.5μg/mL;compounds 1, 2,6,21,and 23-24 caused weak curling deformation,with MIC of 1.6,3.1,3.1,50,12.5 and 1.6μg/mL,respectively;compounds 3-5,7,9,11-13,16-17,20,22,25,and 27-32 showed no deformation effect,and the MIC values were between 0.31-400μg/mL;other compounds showed little effect against P.oryzae P-2b.Compounds 9-11,18-19,and 21 were shown to induce neuronal differentiation in rat PC12 cells,while compounds 1-8 and 20 showed cytotoxic activity against rat PC12 cells.
The bioactivity of those compounds against P.oryzae P-2b in our study was in accordance with the antifungal or cytotoxic effects reported by other researchers,thus the P. oryzae model was proved to be efficient in guiding the seperation of bioactive metabolites from marine-derived fungi.
引文
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