摘要
近年来,由于从陆生生物资源发现新的活性代谢产物的几率越来越低,人们开始把研究热点转移到了生态和物种远比陆地生境复杂多样的海洋。海洋真菌作为海洋生境的重要成员,由于其在海洋生境中所处的独特地位,具有特殊的代谢途径,能够产生结构独特、骨架新颖、活性多样的次级代谢产物,已成为天然产物研究中一个引人注目的焦点。
本文对来源于福建海域的7株海洋真菌(4株红树植物内生真菌HTF3,BYY-1,A-1-5-4,C-2-4-7和3株海藻共附生真菌hzla01-1,PT2,B5)的次级代谢产物进行了研究,从其发酵产物中分离鉴定了61个化合物(包括5个乙酰化产物),其中有15个是新化合物,有7个化合物为首次从红树林真菌中分离得到的,1个化合物为首次从海藻真菌中分离得到。对其中部分化合物的生物活性进行了检测,发现新化合物D23、D28、B3和已知化合物B1的抗肿瘤活性很强,并且B1和B3在一定浓度下能诱导Hela细胞发生显著凋亡;B1和B3还具有很强的抗氧化作用;新化合物hz8、hx和已知化合物D5显示出较高的抗菌活性,具有潜在的应用前景。
对HTF3菌株的次级代谢产物进行了分离纯化,通过核磁共振、质谱及X-Ray单晶衍射分析,鉴定了26个化合物的结构,包括聚酮类化合物、生物碱类化合物、糖酯类化合物、甾醇类化合物等。其中D15、D23、D28、D29、d4c为新聚酮类化合物,命名为dothiorelones E-I;d4e为新糖酯类化合物;D12、HE12和d12a为首次从红树林真菌中分离得到的聚酮类化合物;D4为首次从红树林真菌中分离得到的生物碱类化合物。初步的生物活性分析显示,新化合物D23和D28对人淋巴瘤Raji细胞的IC_(50)小于2μg/mL;已知化合物D5对啤酒酵母的MIC为1.56μg/mL。
从BYY-1菌株中分离鉴定了19个化合物,包括18个聚酮类化合物和1个生物碱。BYY-1菌株中的聚酮类化合物以C_7聚四酮为主,其中还有2个C_7聚四酮聚合为联苯化合物。其中B2、B3、B22、B2A、B3A为新化合物;B27和B35为首次从红树林真菌中分离得到的化合物。对其中1个新联苯化合物(B3)和2个已知C_7聚四酮化合物(B1和B9)的抗菌、抗氧化和抗肿瘤活性进行了测定。结果表明,3个化合物具有较强的抗真菌活性,而抗细菌活性较弱;化合物B1和B3对有机自由基DPPH具有很强的清除作用;化合物B1和B3还具有很强的细胞毒作用,对Hela细胞的IC_(50)分别为3.3μg/mL和3.2μg/mL。初步研究了化合物B1和B3的抗肿瘤作用机理,发现在一定浓度下,化合物B1和B3能诱导Hela细胞发生显著凋亡。化合物B1和B3的抗菌、抗肿瘤作用及机理为首次报道。
从A-1-5-4菌株中分离鉴定了3个聚酮类化合物(A、W1、W2)。化合物A为松孢菌素类化合物,化合物W1为10元大环内酯类化合物,化合物W2为真菌环氧二烯类化合物,并且目前发现的该类化合物只有两个。
从C-24-7菌株中分离鉴定了1个聚酮类化合物(CM2),本文首次报道从红树林真菌中分离得到该化合物。
从hzla01-1菌株中分离鉴定了5个化合物,其中hz8、hz14、hx为新聚酮类化合物,hz7为松孢菌素类化合物,hz11为过氧化麦角甾醇。对其中2个新化合物(hz8和hx)的抗菌、抗氧化和抗肿瘤活性进行了测定。结果表明,化合物hz8和hx具有较高的抗菌活性,其中hz8对大肠杆菌的MIC为5μg/mL,hx对大肠杆菌和枯草芽孢杆菌的MIC分别为5μg/mL和1.25μg/mL。
从PT2菌株中分离鉴定了3个化合物,其中pt1为新倍半萜糖苷类化合物,pt2a为聚酮类化合物,是一种植物生长抑制剂,并且表现出很好的抗菌活性;此外还被用于食品添加剂,本文首次报道从海藻真菌中分离到该化合物。化合物pt2为甘露醇。
从B5菌株中分离鉴定了4个化合物,ab11、ab12分别为不饱和脂肪酸和不饱和脂肪酸甘油酯,ab7和ab10为甾醇类化合物。
本文首次通过饲喂sodium acetate-2-~(13)C和D-Glucose-~(13)C_6的方法研究了化合物D5和B的生物合成途径。结果表明,化合物D5是以乙酸为起始单位和碳链延伸单位的八酮,化合物B是在合成过程中以二碳单位延伸的四酮,并推测了其生物合成途径,为进一步对它们进行开发研究提供了理论依据。
采用形态学和分子生物学的鉴定方法对A-1-5-4、hzla01-1和PT2菌株进行了鉴定。结果表明,A-1-5-4和hzla01-1菌株为拟茎点霉(Phomopsis sp.);PT2菌株为一种木霉菌(Trichoderma sp.)。
本文的结果表明,海洋真菌中蕴藏着丰富的抗菌、抗肿瘤、抗氧化等活性物质产生菌,是开发新药的宝贵的真菌资源,是结构新颖和新的生理活性物质的重要来源。
In recent years, the hot spot has been focused on the much more complex marine resources because of the decrease of discovering novel bioactive metabolites from terrestrial organisms. During adapting to oceanic ecosystem, marine fungi can produce numerous secondary metabolites with unique structures, novel skeletons and varied bioactivities. So marine fungi have attracted more and more attention of the natural products chemist.
In this study, the secondary metabolites of seven marine fungal strains including four endophytic strains of mangroves (HTF3, BYY-1, A-1-5-4, C-2-4-7) and three strains of marine algicolous fungi (hzla01-1, PT2, B5) were studied. Totally, 61 compounds were isolated and identified from the seven strains, including 15 new compounds, 7 compounds isolated from mangrove fungi for the first time and one compound isolated from marine algicolous fungi for the first time. The bioactivities of partial compounds were studied. New compounds D23, D28, B3 and known compound B1 exhibited significant anticancer activities, additionally, compounds B1 and B3 could induce Hela cell apoptosis by FCM analysis; Compounds B1 and B3 showed very strong antioxidant activities. New compounds hz8, hx and known compound D5 exhibited marked antimicrobial activities, indicating that these compounds have potential values in applications.
The secondary metabolites of the strain HTF3 were studied and structures of 26 compounds were elucidated by extensive spectroscopic data analyses and X-ray crystallographic analysis. Five of them were new polyketides, namely D15, D23, D28, D29, d4c, named dothiorelones E-I, respectively. Compound d4e was one new sugar ester. Compounds D12, HE12 and d12a were polyketides isolated from mangrove fungi for the first time, and another compound, namely D4, was alkaloid obtained from mangrove fungi for the first time. New compounds D23 and D28 exhibited cytotoxicities agaist Raji cell with IC_(50) less than 2μg/mL The MIC values of compound D5 against Saccharomyces cerevisiae was 1.56μg/mL
Nineteen compounds were isolated and identified from the strain BYY-1, including eighteen polyketides and one alkaloid. Most polyketides were C_7 tetraketides, and two C_7 tetraketides (B3 and B35) were diphenyl compounds by polymerization. B2, B3, B22, B2A and B3A were new compounds, and compounds B27 and B35 were isolated from mangrove fungi for the first time. The antimicrobe, antioxidant and anticancer activities of one new diphenyl compound (B3) and two known C7 tetraketides (B1 and B9) were studied. The results indicated that three compounds showed stronger antifungal activities and weak antibacterial activities. The DPPH radical scavenging effects of compounds B1 and B3 were notable. Compouds B1 and B3 exhibited cytotoxicities agaist Hela cell with IC50 3.3μ/mL and 3.2μg/mL, respectively; additionally, compounds B1 and B3 could induce Hela cell apoptosis by FCM analysis. The antimicrobe activities, anticancer activities and mechanisms of compounds B1 and B3 were first reported.
Three polyketides (A, W1 and W2) were isolated and identified from the strain A-1-5-4. Compound A was cytochalasin H; W1 was 10-membered macrolactone; W2 was mycoepoxydiene and at present there were only two mycoepoxydiene all over the world.
One polyketide (CM2) was isolated and identified from the strain C-2-4-7, and it was isolated from mangrove fungi for the first time.
Five compounds were isolated and identified from the strain hzla01-1, including three new polyketides (hz8, hz14 and hx), one cytochalasin (hz7) and one sterol derivative (hz11). Two new compounds (hz8 and hx) exhibited potent antimicrobe activities. The MIC value of compound hz8 against Escherichia coli was 5μg/mL, and the MIC values of compound hx against Escherichia coli, Bacillus subtilis were 5μg/mL, 1.25μg/mL, respectively.
Three compounds were isolated and identified from the strain PT2. Compound pt1 was new sesquiterpene glucoside; compound pt2a was polyketide and it was isolated from marine algicolous fungi for the first time. It was reported that compound pt2a was used as a plant growth inhibitory and a food additive, it also exhibited antimicrobial activity. Compound pt2 was hexane-1,2,3,4,5,6-hexaol.
Four compounds were isolated and identified from the strain B5, including one unsaturated fatty acids, one derivative of unsaturated fatty acids and two sterols derivatives.
The biosynthesis pathways of compounds D5 and B were first studied by feeding sodium acetate-2-~(13)C and D-glucose-~(13)C_6. The results indicated compound D5 was octaketide using acetic acid to carbon-chain assembly; compound B was tetraketide and its biosynthesis with two-carbon extension. We speculated the biosynthesis pathways of compounds D5 and B.
The strains A-1-5-4, hzla01-1 and PT2 were identified by morphological and molecule biological methods. The result indicated that the strain A-1-5-4 and the strain hzla01-1 belonged to Phomopsis sp., and the strain PT2 belonged to Trichoderma sp..
In conclusion, our study indicated that marine fungi were valuable resources for novel metabolites with antimicrobial, antitumor and antioxidant activities.
引文
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