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热带海洋学报 >

2019 , Vol. 38 >Issue 2: 43 - 47

DOI: https://doi.org/10.11978/2018072

海洋生物学

中国南海软珊瑚真菌Eupenicillium sp. DX-SER3 (KC871024)的次级代谢产物研究

  • 谭雁鸿 , 1, 2 ,
  • 李基兴 1, 2 ,
  • 林秀萍 2 ,
  • 杨斌 2 ,
  • 刘永宏 , 2 ,
  • 李云秋 , 1
展开
  • 1. 桂林医学院药学院, 广西 桂林 541004
  • 2. 中国科学院南海海洋研究所热带海洋生物资源与生态重点实验室, 广东 广州 510301
通信作者：刘永宏, E-mail: ; 李云秋, E-mail:

作者简介：谭雁鸿(1994—), 男, 江西省赣州市人, 硕士, 从事天然药物化学研究。E-mail:

收稿日期: 2018-07-20

  要求修回日期: 2018-09-02

  网络出版日期: 2019-04-15

基金资助

国家自然科学基金项目(81741158、20062115)

广州市科技计划项目(201804010462)

收起

Study on the secondary metabolites from the South China Sea soft coral-derived fungus Eupenicillium sp. DX-SER3 (KC871024)

  • TAN Yanhong , 1, 2 ,
  • LI Jixing 1, 2 ,
  • LIN Xiuping 2 ,
  • YANG Bin 2 ,
  • LIU Yonghong , 2 ,
  • LI Yunqiu , 1
Expand
  • 1. College of Pharmacy, Guilin Medical University, Guilin 541004, China
  • 2. Key Laboratory of Tropical Marine Bio-resources and Ecology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China
Corresponding author: LIU Yonghong. E-mail: LI Yunqiu. E-mail:

Received date: 2018-07-20

  Request revised date: 2018-09-02

  Online published: 2019-04-15

Supported by

National Natural Science Foundation of China (81741158, 20062115)

Guangzhou Science and Technology Plan Project (201804010462)

Copyright

热带海洋学报编辑部
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摘要

文章旨在对中国南海软珊瑚来源真菌Eupenicillium sp. DX-SER3 (KC871024)进行次级代谢产物的研究。利用硅胶层析柱、正反相中压层析柱以及半制备高效液相等方法对该菌株的大米发酵产物进行分离纯化, 利用核磁共振、质谱等波谱学方法并参考文献数据对分离的单体化合物进行结构鉴定。从中分离得到5个已知化合物: 烟曲霉酸、β-腺苷、2'-脱氧胸腺嘧啶核苷、N-acyltryptamine和对羟基苯甲醛。其中, 烟曲霉酸在该菌株中产量很高, 预示着该菌株具有开发成该类化合物的工程菌株的潜力。文章还探讨了烟曲霉酸抗植物病原真菌的潜力, 发现效果并不明显。

关键词： 中国南海; 软珊瑚; Eupenicillium sp.; 次级代谢产物

本文引用格式

谭雁鸿 , 李基兴 , 林秀萍 , 杨斌 , 刘永宏 , 李云秋 . 中国南海软珊瑚真菌Eupenicillium sp. DX-SER3 (KC871024)的次级代谢产物研究[J]. 热带海洋学报, 2019 , 38(2) : 43 -47 . DOI: 10.11978/2018072

Abstract

We aim to study the secondary metabolites from the South China Sea soft coral-derived fungus Eupenicillium sp. DX-SER3 (KC871024). The rice fermentation products of the strain were purified by comprehensive chromatography methods of silica gel column, medium pressure preparative liquid chromatography (MPLC), ostade-cylsilane (ODS), and semi- preparative HPLC. The compounds’ structures were identified by nuclear magnetic resonance spectroscopy, mass spectroscopy, and comparison with the reported data. Five known compounds were obtained and identified as helvolic acid, β-adenosine, 2'-deoxythymidine, N-acyltryptamine, and p-hydroxybenzaldehyde. The high yield of the helvolic acid indicates that this strain has the potential to develop an engineered strain of this kind of compound. Helvolic acid was also tested for the activities of phytopathogenic fungus, and the result was not clear.

Key words： South China Sea; soft coral; Eupenicillium sp.; secondary metabolites

广阔的海洋孕育着极其丰富的生物资源, 作为一种常见的海洋无脊椎动物, 软珊瑚及其共附生微生物已经成为海洋天然产物研究的重要对象(邢倩, 2014)。随着微生物采集技术、化合物分离纯化及波谱解析技术的进步, 越来越多的海洋天然产物的化学结构得以被发现并解析, 并且成为药物先导化合物的重要来源(Li et al, 2015), 具有良好的生物活性, 如抗菌、抗肿瘤、抗污等(田永奇 等, 2017)。青霉属(Penicillium)是海洋真菌的第二大种类, 属于子囊菌亚门, 不整囊菌纲, 散囊菌目, 散囊菌科, 也是海洋天然产物的重要源泉。正青霉属(Eupenicillium sp.)是青霉属真菌的一个重要分支, 目前国内外对从软珊瑚来源的正青霉属真菌还未有深入研究, 其次级代谢产物研究也报道较少。
Zheng等(2018)从红树林来源真菌Eupenicillium sp. HJ002中分离得到3个新型吲哚二萜类化合物penicilindoles A~C, 其中penicilindole A 对A549与HepG2肿瘤细胞具抑制活性, 50%抑菌浓度(IC50)值分别为5.5μM和1.5μM; Gu等(2018)从海绵来源真菌Eupenicillium sp. 6A-9中分离得到比较罕见的萜类成分eupeniacetal A、eupeniacetal B、1-oxymethyl- hydropreaustinoid A1、hydroberkeleyone B和22-deoxy-10-ketominiolutelide B, 这些化合物均显示出对TNF-α产物诱导THP-1细胞系凋亡的抑制活性, 但对正常肿瘤细胞系无明显活性; Li等(2017)从植物内生真菌分出的Eupenicillium sp. LG41中分离得到十氢化萘类结构eupenicinicols C和D, eupenicinicols D显示出抗金黄色葡萄球菌活性。本文报道了从中国南海软珊瑚来源真菌Eupenicillium sp.的大米发酵产物中分离的5个化合物(图1)。
Fig. 1 The chemical structures of compounds 1-5

图1 分离得到5个化合物的化学结构
1. 烟曲霉酸; 2. β-腺苷; 3. 2'-脱氧胸腺嘧啶核苷; 4. N-acyltryptamine; 5. 对羟基苯甲醛

1 材料与方法

1.1 仪器与试剂

主要仪器包括旋转蒸发仪(EYELAN-1100V-W型,日本东京理化株式会社)、AV-500和AV-700核磁共振仪(德国Brucker公司)、HITACHI L-2400半制备HPLC (日本日立公司)、ZYJ-S型超净工作台(苏州净化设备有限公司)、中压制备柱色谱仪(Buchi公司产品C615/605)、HR-ESM-MS (德国Brucker公司)。主要试剂包括薄层色谱硅胶(青岛海洋化工厂)、10~40和100~200正相硅胶(烟台江友硅胶开发有限公司)、反相硅胶(Merck公司)及分析纯级化学试剂(广州化学试剂厂和天津市富宇精细化工有限公司)等。

1.2 菌株发酵培养

供试软珊瑚附生菌株Eupenicillium sp. DX- SER3 (KC871024)保存于4℃环境。该菌株接种到PDA琼脂固体斜面培养基上, 置于28℃培养箱培养7d。用接种针挑取适量孢子, 接种到含15mL MB培养液(麦芽粉15g, 海盐2.5g, 蒸馏水1000mL, PH 7.4~7.8)的150mL三角烧瓶中, 在25℃, 180r•min-1摇床条件下培养3d。将培养好的种子液分别接种到40瓶灭菌后的大米培养基(大米200g, 海盐2.5g, 蒸馏水250mL)中静置培养60d。

1.3 提取分离纯化

发酵完毕后菌株用两倍体积丙酮浸泡2d, 然后将大米捣碎, 超声20min, 用纱布进行过滤, 滤液减压浓缩以除去丙酮, 然后再用两倍体积乙酸乙酯萃取3次, 浓缩后得到乙酸乙酯粗浸膏, 滤渣继续用乙酸乙酯提取3遍, 浓缩后合并以上乙酸乙酯部分得总粗浸膏。粗浸膏采用中压色谱进行分离, 用100~200目硅胶拌样, 流动相为石油醚 : 乙酸乙酯(V : V 100 : 0 ~ 1 : 1, 流速50mL•min-1)梯度洗脱得到第一部分, 为42.5L, 再用石油醚 : 乙酸乙酯 :甲醇(V : V : V 20 : 20 : 1 ~ 0 : 0: 100, 流速50mL•min-1)梯度洗脱得到第二部分, 为17.5L。两部分通过薄层色谱法(TLC)检识合并得18个馏分。其中Fraction (5、7、9、11、15)经反相中压色谱(ODS)(MeOH : H2O 20 : 80 ~ 100 : 0)梯度洗脱, Frc.5分得13个子馏分, 其中Frc.5-2用半制备液相(MeOH : H2O 25 : 75)分离得到化合物5 (2.4mg), Frc.5-13用半制备液相色谱分离(MeOH : H2O 92 : 8)得到化合物2 (12.7mg); Frc.7经反复结晶得到化合物1 (1200mg); Frc.11分得15个子馏分, 其中Frc.11-7用半制备液相(MeOH : H2O 30 : 70)分离得到化合物4 (3.5mg); Frc.15分得8个子馏分, 其中Frc.15-7经半制备液相(MeOH : H2O 5 : 95)分离得到化合物3 (6.4mg)。

2 结果

2.1 化合物1的结构鉴定

白色结晶; 1H-NMR (500MHz, CDCl3) δ: 7.32 (1H, d, J = 10.0Hz, H-1), 5.90 (1H, d, J = 9.5Hz, H-16), 5.88 (1H, d, J = 10Hz, H-2), 5.11 (1H, t, J = 7.0Hz, H-24), 3.49 (1H, brs, H-6), 2.77 (1H, q, J = 7.0Hz, H-4), 2.63 (1H, dd, J = 13.0, 3.0Hz, H-9), 2.57 (1H, m, H-13), 2.44 (2H, m, H-22), 2.26 (1H, d, J = 12.0Hz, H-5), 2.23 (2H, d, J = 8.5Hz, H-15), 2.11 (3H, s, H-2'), 2.10 (2H, m, H-23), 1.96 (3H, s, H-2''), 1.93 (2H, d, J = 14.5Hz, H-15), 1.83 (2H, dd, J = 12.5, 3.5Hz, H-12), 1.69 (3H, s, H-27), 1.61 (3H, s, H-26), 1.57 (2H, m, H-11), 1.45 (3H, s, H-19), 1.28 (3H, d, J = 7Hz, H-28), 1.18 (3H, s, H-29), 0.93(3H, s, H-18); 13C-NMR (CDCl3, 125 MHz) δ: 208.8 (C, C-7), 201.3 (C, C-3), 174.1 (C, C-21), 170.3 (C, C-1''), 168.9 (C, C-1'), 157.2 (CH, C-1), 147.4 (C, C-17), 132.9 (C, C-25), 130.5 (C, C-20), 127.9 (CH, C-2), 122.8 (CH, C-24), 73.8 (CH, C-6), 73.5 (CH, C-16), 52.7 (C, C-8), 49.4 (CH, C-13), 47.2 (CH, C-5), 46.6 (C, C-14), 41.7 (C, C-9), 40.7 (CH2, C-15), 40.4 (CH, C-4), 38.2 (C, C-10), 28.6 (CH2, C-22), 28.3 (CH2, C-23), 27.5 (CH3, C-19), 25.9 (CH2, C-12), 25.7 (CH3, C-27), 23.9 (CH2, C-11), 20.7 (CH3, C-2'), 20.5 (CH3, C-2''), 18.3 (CH3, C-29), 17.9 (CH3, C-18), 17.8 (CH3, C-26), 13.1 (CH3, C-28)。以上数据与文献(Fujimoto et al, 1996)对照一致, 故确定化合物1为烟曲霉酸。

2.2 化合物2的结构鉴定

黄色固体; 1H-NMR (500MHz, DMSO-d6) δ: 3.54 (2H, s, NH2), 3.64 (2H, m, H-5'), 3.94 (1H, q, J = 3.5Hz, H-4'), 4.13 (1H, m, H-3'), 4.56 (1H, t, J = 5.0Hz, H-2'), 5.19 (1H, brs, OH-3'), 5.42 (1H, m, OH-2'), 5.45 (1H, m, OH-5'), 5.87 (1H, d, J = 6.5Hz, H-1'), 8.12 (1H, s, H-2), 8.33 (1H, s, H-8); 13C-NMR (DMSO-d6, 125MHz) δ: 61.9 (CH2, C-5'), 70.8 (CH, C-3'), 73.6 (CH, C-2'), 86.1 (CH, C-4'), 88.1 (CH, C-1'), 119.5 (C, C-5), 140.1 (CH, C-8), 149.2 (C, C-4), 152.6 (CH, C-2), 156.3 (C, C-6)。以上数据与文献(Domondon et al, 2004)一致, 故确定化合物2为β-腺苷。

2.3 化合物3的结构鉴定

褐色固体; 1H-NMR (500MHz, DMSO-d6) δ: 1.74 (3H, s, CH3), 2.03 (1H, m, H-2'a), 2.06 (1H, m, H-2'b), 3.33 (2H, brs, H-5'), 3.58 (1H, ddd, J = 3.5, 4, 12Hz, H-4'), 4.22 (1H, m, H-3'), 5.07 (1H, m, 5'-OH), 5.27 (1H, m, 3'-OH), 6.16 (1H, dd, J = 6.5, 7.5Hz, H-1'), 7.64 (1H, s, H-6), 11.21 (1H, s, NH); 13C-NMR (DMSO-d6, 125MHz) δ: 12.4 (CH3, C-7), 39.4 (CH2, C-2'), 61.3 (CH2, C-5'), 70.4 (CH, C-3'), 83.8 (CH, C-1'), 87.2 (CH, C-4'), 109.3 (C, C-5), 136.0 (CH, C-6), 151.1 (C, C-4), 164.7 (C, C-2)。以上数据与文献(刘培培 等, 2008)一致, 故确认该化合物为2'-脱氧胸腺嘧啶核苷。

2.4 化合物4的结构鉴定

褐色粉末; 1H-NMR (700MHz, DMSO-d6) δ: 1.80 (3H, s, CH3), 2.81 (2H, t, J = 7.7Hz, H-10), 3.32 (2H, dd, H-11), 6.98 (1H, t, J = 7.7Hz, H-5), 7.07 (1H, t, J = 7.0Hz, H-6), 7.14 (1H, d, H-2), 7.34 (1H, d, J = 7.7Hz, H-4), 7.52 (1H, d, J = 7.7Hz, H-7), 7.95 (1H, t, NH-12), 10.82 (1H, s, NH-1); 13C-NMR (DMSO-d6, 175MHz) δ: 22.3 (CH3, C-14), 24.9 (CH2, C-10), 39.7 (CH2, C-11), 111.0 (CH, C-3), 111.5 (C, C-7), 117.8 (CH, C-4), 120.5 (CH, C-5), 122.2 (CH, C-6), 126.9 (C, C-9), 135.9 (C, C-8), 168.7 (C, C-13)。以上数据与文献(Oleinikova et al, 2006)一致, 故确认该结构为N-Acyltryptamine。

2.5 化合物5的结构鉴定

淡黄色固体; 1H-NMR (500MHz, CD3OD) δ: 6.95 (2H, d, J = 10Hz, H-2和H-6), 7.81 (2H, d, J = 10Hz, H-3和H-5), 9.79 (1H, s, H-7)。以上数据与文献(赵爱华 等, 2004)一致, 故确定为对羟基苯甲醛。

3 讨论

本课题组从南海软珊瑚真菌Eupenicillium sp.大米发酵产物中分离鉴定了5个化合物, 包含1个抗生素(烟曲霉酸)、1个吲哚生物碱(N-acyltryptamine)、2个核苷酸和1个含苯衍生物。菌株Eupenicillium sp. SCSIO41205是从三沙市七连屿附近海域采集的短指软珊瑚中分离的一株真菌, 通过HPLC分析和代谢产物的分离, 发现该菌的大米固体发酵液中代谢产物十分单一, 主要产物为烟曲霉酸, 含量很高, 从8kg大米固体发酵液中得到1.2g。Chain等(1943)从100L烟曲霉菌的液体培养基中分得烟曲霉酸0.4g; Ratnaweera等(2014)从2.25L炭角菌的PDA液体培养基中分得烟曲霉酸3mg; Sanmanoch等(2016)从10L新萨托菌属的MB液体培养基中分得烟曲霉酸0.2g。本文研究真菌正青霉属分得烟曲霉酸含量远远高于其他菌属, 且易于分离, 因此该菌株可以作为生产烟曲霉酸的工业菌株。烟曲霉酸因具有良好的抗菌活性和显著的抗肿瘤活性而受到广泛关注。据报道, 烟曲霉酸于1942年首次从烟曲霉菌Aspergillus fumigatus代谢产物中分离得到并命名(Chain et al, 1943)。Xiao等(2017)从冬虫夏草分离到的烟曲霉酸对不同人体癌细胞(胰腺、子宫、肝脏、肺)显示出有效抑制活性, 并且10mg•kg-1剂量烟曲霉酸结合20mg•kg-1环磷酰胺在体外展现较强抗癌活性的协同作用, 其肿瘤生长抑制率达到70.90%。Luo等(2017)从深海曲霉真菌Aspergillus sp. SCSIO Ind09F01中分离得到的烟曲霉酸具有抗痨作用, 并对结核杆菌有非常强的抑制活性, 50%最低抑菌浓度(MIC50)值小于0.894μM。作为一种抑菌剂, Sanmanoch等(2016)从新萨托土壤真菌Neosartorya spinosa KKU-1NK1乙酸乙酯提取部位分离得到的烟曲霉酸测试了对革兰氏阳性菌与阴性菌的抑制活性, 结果对革兰氏阳性致病菌株包括耐甲氧西林金黄色葡萄球菌DMST 20654、金黄色葡萄球菌ATCC 25923、腐生葡萄球菌ATCC 15305、肺炎链球菌DMST 15319、粪肠球菌ATCC 29212、枯草芽孢杆菌ATCC 6633和阴性致病菌株包括青枯雷尔氏菌、野油菜黄单胞菌vesicatoria都具有抑制活性, 其最小抑菌浓度(MIC)值都在16~32μg•mL-1范围内。Ratnaweera等(2014)通过色谱层析法从植物内生真菌炭角菌中分离得到的烟曲霉酸对革兰氏阳性菌枯草杆菌与抗药性金黄色葡萄球菌具有抑制活性, 其MIC值分别为2μg•mL-1与4μg•mL-1。此外有文献报道该化合物对胆固醇的累积有一定抑制作用(Shinohara et al, 1993)。为了探讨该化合物在农用抗菌的应用潜力, 我们通过纸片法测试该化合物对5种植物致病菌(水稻稻瘟菌Pyricularia oryzae Cav、芒果炭疽菌C. asianum T0408、橡胶炭疽菌C. gloeosporioides RC178、香蕉枯萎杆菌F. oxysporum f. sp. cubense race 4、薯蓣炭疽菌C. gloeosporioides Cg9)的抑制活性, 结果该化合物并不显示抑制活性。
正青霉菌来源较为广泛, 从植物来源包含植物外皮组织、植物根茎与种子, 动物来源, 土壤来源以及其他来源如其他真菌代谢与衍生物等都可获得。其中以土壤来源和植物组织中来源正青霉属种类最多(季波 等, 2017)。本文研究软珊瑚来源正青霉属真菌除烟曲霉酸外, 包含的两个核苷酸和一个含苯衍生物在自然界中都较为常见, 以及一个吲哚生物碱N-acyltryptamine。Oleinikova等(2006)中发现N-acyltryptamine具有微弱抗Erlich肿瘤细胞活性和溶血活性, 而在破坏深海海胆S. intermedius卵细胞膜与精子细胞膜实验中没有展现出活性, MIC大于50μg•mL-1。

The authors have declared that no competing interests exist.

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JI BO, XIAO YIWEN, ZHU DU, et al, 2017. Review on secondary metabolites from Eupenicillium fungi[J]. Natural Product Research and Development, 29(4): 686-694 (in Chinese with English abstract).

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刘培培, 陶洪文, 吴芬, 等, 2008. 裸体方格星虫甲醇提取物的化学成分研究[J]. 中国海洋药物, 27(5): 28-30.目的对裸体方格星虫（Sipunculus nudus Linnaeus）甲醇提取物的化学成分进行分离鉴定。方法采用溶剂萃取．硅胶柱色谱及半制备HPLC等分离手段对其甲醇提取物的化合物进行分离．通过理化性质及波谱学手段对所得化合物进行化学结构鉴定。结果与结论分离并鉴定了4个化合物：胆甾醇（1）、硬脂酸（2）、环（丙氨酸-脯氨酸）（3）、脱氧胸苷（4）．这4个化合物均为首次从裸体方格星虫中分离得到。

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LIU PEIPEI, TAO HONGWEN, WU FEN, et al, 2008. Study on the chemical constituents of methanol extracts from Sipunculus nudus[J]. Chinese Journal of Marine Drugs, 27(5): 28-30 (in Chinese with English abstract).

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田永奇, 林圣楠, 周洪, 等, 2017. 深海来源真菌Aspergillus sp. SCSIO Ind09F01代谢产物的研究[J]. 天然产物研究与开发, 29(9): 1512-1516, 1528.利用硅胶柱色谱 、凝胶柱、反向柱色谱和高效液相等手段对深海来源的真菌 sp. S CSIO Ind09F01的代谢产物进行分离纯化,从中分离得到了 1 3个化合物.通过理化性质、波谱分析方法结合文献对 照,鉴定了化合物的结构分别为：sydowinin B （ 1）、 pinselin（ 2）、 1, 6 -dihydroxy-3- methyl-8-carbom ethoxyxanthone （3）、 MT-1 （4）、 l-hydroxy-6,8-dimethoxy-3-methyl-9, 10-anthraquin o n e （ 5 ）、methyl orsellinate（6）、 orcinol（7）、 mrlac- tonel（8）、Janthinone （ 9 ）、 cyclo-（ L-trptophyl-L-phenylalanyl） （ 10 ）、 13-0-acetylsydowinin B （ 11）、 7-Hydroxy-2, 5- dimethylchromone（12）、 Acremolin（13）

TIAN YONGQI, LIN SHENGNAN, ZHOU HONG, et al, 2017. Metabolites from the deep-sea-derived fungus Aspergillus sp. SCSIO Ind09F01[J]. Natural Product Research and Development, 29(9): 1512-1516, 1528 (in Chinese with English abstract).

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邢倩, 2014. 一株软珊瑚来源真菌Pestalotiopsis sp. 氯代二苯甲酮类化合物及其生物活性研究[D]. 青岛: 中国海洋大学: 6-7.

XING QIAN, 2014. Chlorinated benzophenone derivatives isolated from a soft coral-derived fungus Pestalotiopsis sp. and their biological activities[D]. Qingdao: Ocen University of China: 6-7 (in Chinese with English abstract).

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ZHAO AIHUA, ZHAO QINSHI, LI RONGTAO, et al, 2004. Chemical Constituents from Clerodendranthus spicatus[J]. Acta Botanica Yunnanica, 26(5): 563-568 (in Chinese with English abstract).

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CHAIN E, FLOREY H W, JENNINGS M A, et al, 1943. Helvolic acid, an antibiotic produced by Aspergillus fumigatus, mut. helvola yuill[J]. British Journal of Experimental Pathology, 24(3): 108-119.

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DOMONDON D L, HE WEIDONG, DE KIMPE N, et al, 2004. β-adenosine, a bioactive compound in grass chaff stimulating mushroom production[J]. Phytochemistry, 65(2): 181-187.

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FUJIMOTO H, NEGISHI E, YAMAGUCHI K, et al, 1996. Isolation of new tremorgenic metabolites from an Ascomycete, Corynascus setosus[J]. Chemical & Pharmaceutical Bulletin, 44(10): 1843-1848.

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GU BINBIN, WU WEI, LIU LIYUN, et al, 2018. 3,5-dimethylorsellinic acid derived meroterpenoids from Eupenicillium sp. 6A-9, a fungus isolated from the marine sponge plakortis simplex[J]. European Journal of Organic Chemistry, 2018(1): 48-59.

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[10]
LI GANG, KUSARI S, GOLZ C, et al, 2017. Epigenetic modulation of endophytic Eupenicillium sp. LG41 by a histone deacetylase inhibitor for production of decalin-containing compounds[J]. Journal of Natural Products, 80(4): 983-988.An endophytic fungus, Eupenicillium sp. LG41, isolated from the Chinese medicinal plant Xanthium sibiricum, was subjected to epigenetic modulation using an NAD+-dependent histone deacetylase (HDAC) inhibitor, nicotinamide. Epigenetic stimulation of the endophyte led to enhanced production of two new decalin-containing compounds, eupenicinicols C and D (3 and 4), along with two biosynthetically related known compounds, eujavanicol A (1) and eupenicinicol A (2). The structures and stereochemistry of the new compounds were elucidated by extensive spectroscopic analysis using LC-HRMS, NMR, optical rotation, and ECD calculations, as well as single-crystal X-ray diffraction. Compounds 3 and 4 exist in chemical equilibrium with two and three cis/trans isomers, respectively, as revealed by LC-MS analysis. Compound 4 was active against Staphylococcus aureus with an MIC of 0.1 g/mL and demonstrated marked cytotoxicity against the human acute monocytic leukemia cell line (THP-1). We have shown that the HDAC inhibit...

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[11]
LI KE, CHUNG-DAVIDSON Y W, BUSSY U, et al, 2015. Recent advances and applications of experimental technologies in marine natural product research[J]. Marine Drugs, 13(5): 2694-2713.Marine natural products are a rich source of novel and biologically active compounds. The number of identified marine natural compounds has grown 20% over the last five years from 2009 to 2013. Several challenges, including sample collection and structure elucidation, have limited the development of this research field. Nonetheless, new approaches, such as sampling strategies for organisms from extreme ocean environments, nanoscale NMR and computational chemistry for structural determination, are now available to overcome the barriers. In this review, we highlight the experimental technology innovations in the field of marine natural products, which in our view will lead to the development of many new drugs in the future.

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[12]
LUO XIAOWEI, ZHOU XUEFENG, LIN XIUPING, et al, 2017. Antituberculosis compounds from a deep-sea-derived fungus Aspergillus sp. SCSIO Ind09F01[J]. Natural Product Research, 31(16): 1958-1962.Eleven diketopiperazine and fumiquinazoline alkaloids (1-11) together with a tetracyclic triterpenoid helvolic acid (12) were obtained from the cultures of a deep-sea derived fungus Aspergillus sp. SCSIO Ind09F01. The structures of these compounds (1-12) were determined mainly by the extensive NMR, ESIMS spectra data and by comparison with previously described compounds. Besides, anti-tuberculosis, cytotoxic, antibacterial, COX-2 inhibitory and antiviral activities of these compounds were evaluated. Gliotoxin (3), 12,13-dihydroxy-fumitremorgin C (11) and helvolic acid (12) exhibited very strong anti-tuberculosis activity towards Mycobacterium tuberculosis with the prominent MIC50 values of <0.03, 2.41 and 0.894M, respectively, which was here reported for the first time. Meanwhile gliotoxin also displayed significant selective cytotoxicities against K562, A549 and Huh-7 cell lines with the IC50 values of 0.191, 0.015 and 95.4M, respectively. [GRAPHICS] .

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[13]
OLEINIKOVA G K, IVCHUK O I, DENISENKO V A, et al, 2006. Indolic metabolites from the new marine bacterium Roseivirga echinicomitans KMM 6058T[J]. Chemistry of Natural Compounds, 42(6): 713-717.

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RATNAWEERA P B, WILLIAMS D E, DE SILVA E D, et al, 2014. Helvolic acid, an antibacterial nortriterpenoid from a fungal endophyte, Xylaria sp. of orchid Anoectochilus setaceus endemic to Sri Lanka[J]. Mycology, 5(1): 23-28.

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SANMANOCH W, MONGKOLTHANARUK W, KANOKMEDHAKUL S, et al, 2016. Helvolic acid, a secondary metabolite produced by Neosartorya spinosa KKU-1NK1 and its biological activities[J]. Chiang Mai Journal of Science, 43(3): 483-493.

[16]
SHINOHARA C, HASUMI K, ENDO A, et al, 1993. Inhibition of oxidized low-density lipoprotein metabolism in macrophage J774 by helvolic acid[J]. Biochimica et Biophysica Acta - Lipids and Lipid Metabolism, 1167(3): 303-306.

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[17]
XIAO JIANHUI, ZHANG YAO, LIANG GUIYOU, et al, 2017. Synergistic antitumor efficacy of antibacterial helvolic acid from Cordyceps taii and cyclophosphamide in a tumor mouse model[J]. Experimental Biology and Medicine, 242(2): 214-222.Abstract The antibacterial agent helvolic acid, which was isolated from the active antitumor fraction of Cordyceps taii, showed potent cytotoxicity against different human cancer cells. In the present study, the in0002vivo antitumor effect of helvolic acid was investigated in murine sarcoma S180 tumor-bearing mice. Doses of 10 and 20090009mg/kg/day helvolic acid did not exert significant antitumor activity. Interestingly, co-administration of 10090009mg/kg/day helvolic acid and 20090009mg/kg/day cyclophosphamide (CTX) - a well-known chemotherapy drug - showed promising antitumor activity with a growth inhibitory rate of 70.90%, which was much higher than that of CTX alone (19.5%). Furthermore, the combination markedly prolonged the survival of tumor-bearing mice. In addition, helvolic acid enhanced the immune organ index. The protein expression levels of 0205-catenin, cyclin D1, and proliferating cell nuclear antigen were significantly suppressed in mice treated with 20090009mg/kg/day helvolic acid and in those receiving combination therapy. Taken together, these results indicated that helvolic acid in combination with CTX showed potent in0002vivo synergistic antitumor efficacy, and its mechanism of action may involve the Wnt/ 0205-catenin signaling pathway.

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[18]
ZHENG CAIYUAN, BAI MENG, ZHOU XUEMING, et al, 2018. Penicilindoles A-C, cytotoxic indole diterpenes from the mangrove-derived fungus Eupenicillium sp. HJ002[J]. Journal of Natural Products, 81(4): 1045-1049.Abstract Three new indole diterpenes, penicilindoles A-C (1-3), were isolated from the mangrove-derived fungus Eupenicillium sp. HJ002. Their planar structures and absolute configurations were determined by interpretation of NMR spectroscopic data, HR-ESIMS, and X-ray diffraction analysis using Cu Kα radiation. The cytotoxic and antibacterial activities were evaluated in vitro; penicilindole A (1) showed cytotoxic activity against human A549 and HepG2 cell lines with IC 50 values of 5.5 and 1.5 μM, respectively.

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