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海洋曲霉来源的新天然产物

本站小编 Free考研考试/2021-12-26
海洋曲霉来源的新天然产物
赵成英, 刘海珊, 朱伟明
中国海洋大学医药学院, 海洋药物教育部重点实验室, 山东 青岛 266003

收稿日期：2015-10-15; 修回日期：2015-12-25; 网络出版日期：2015-12-30
资助课题：国家自然科学基金(41376148,81561148012,U1406402-1,U1501221)
通讯作者：朱伟明, Tel/Fax:+86-532-82031836;E-mail:weimingzhu@ouc.edu.cn


摘要: 海洋真菌由于其遗传背景复杂、代谢产物种类多且产量高,已成为海洋微生物新天然产物的主要来源,从我们对2010-2013年初的海洋微生物来源新天然产物的统计来看,研究最多的是曲霉属(Aspergillus)真菌,占海洋真菌来源新天然产物的31%。本文从菌株来源、化合物结构及其生物活性等方面,综述了自1992年第一个海洋曲霉天然产物到2014年8月已报道的共512个海洋曲霉来源的新天然产物。这些海洋天然产物具有丰富的化学多样性,且36%的化合物表现出细胞毒、抑菌、抗氧化和抗寄生虫等生物活性;含氮化合物是其主要的结构类型、约占曲霉源海洋天然产物总数的52%,也是出现活性化合物比例最高的结构类型、约40%的含氮化合物具有生物活性,其中脱氢二酮哌嗪生物碱halimide的化学衍生物plinabulin已结束II期临床研究,并于2015年第三季度开始在美国和中国进行III期临床研究,用于治疗转移性的晚期非小细胞肺癌。
关键词: 海洋真菌曲霉天然产物化学结构生物活性来源
New natural products from the marine-derived Aspergillus fungi-A review
Chengying Zhao, Haishan Liu, Weiming Zhu
Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, Shandong Province, China
Supported by the National Natural Science Foundation of China (41376148, 81561148012, U1406402-1, U1501221)
Corresponding author. Weiming Zhu, Tel/Fax:+86-532-82031836;E-mail:weimingzhu@ouc.edu.cn


Abstract:Marine-derived fungi were the main source of marine microbial natural products (NPs) due to their complex genetic background, chemodiversity and high yield of NPs. According to our previous survey for marine microbial NPs from 2010 to 2013, Aspergillus fungi have received the most of attention among all the marine-derived fungi, which accounted for 31% NPs of the marine fungal origins. This paper reviewed the sources, chemical structures and bioactivites of all the 512 new marine NPs of Aspergillus fungal origins from 1992 to 2014. These marine NPs have diverse chemical structures including polyketides, fatty acids, sterols and terpenoids, alkaloids, peptides, and so on, 36% of which displayed bioactivities such as cytotoxicity, antimicrobial activity, antioxidant and insecticidal activity. Nitrogen compounds are the major secondary metabolites accounting for 52% NPs from the marine-derived Aspergillus fungi. Nitrogen compounds are also the class with the highest ratio of bioactive compounds, 40% of which are bioactive. Plinabulin, a dehydrodiketopiperazine derivative of halimide had been ended its phase II trial and has received its phase III study from the third quarter of 2015 for the treatment of advanced, metastatic non-small cell lung cancer.
Key words: marine-derived fungiAspergillus sp.natural productschemical structuresbioactivitiessources
海洋真菌由于其遗传背景复杂、代谢产物种类多、产量高，成为海洋微生物新天然产物的主要来源，作者对2010-2013年初的海洋微生物来源新天然产物的统计表明，研究最多的真菌属是曲霉(Aspergillus)，占海洋真菌新天然产物的31%[1]。海洋曲霉源天然产物的研究始于1992年，Shinggu等报道了首例海洋曲霉来源的新天然产物fumiquinazolines A-C (149-151)[2]；截止到2014年8月，已报道512个海洋曲霉来源的新天然产物。其结构类型多样(包括聚酮、生物碱、萜类、甾体、卤代物、脂肪酸、肽类、糖苷等)，且有多种生物活性(包括抗癌、抑菌、自由基清除和抗寄生虫等)。值得一提的是，由海洋曲霉天然产物halimide(301)[3, 4]衍生而来的plinabulin (NPI-2358)[5]是一种血管阻断剂，作用于肿瘤细胞，影响微管蛋白解聚；目前plinabulin已结束II期临床研究、开始在美国和中国进行III期临床研究，用于治疗转移性的晚期非小细胞肺癌(NSCLC)[6]，成为20个海洋药物之一，也是唯一的海洋曲霉菌来源的药物[7]。由此可见海洋曲霉是海洋天然产物乃至新药发现的重要资源，本文将综述这些海洋曲霉新天然产物的菌株来源、结构及其生物活性。
1 海洋动物来源的曲霉天然产物1.1 海绵来源的曲霉天然产物氯代物chlorocarolides A(1)和B(2)来源于赫曲霉Aspergillus cf.ochraceus 941026[8]。1株黑曲霉Aspergillus niger代谢产生二酮哌嗪(环缩二氨酸)的二聚体asperazine(3)，该化合物可以选择性抑制人白血病细胞L1210、C38以及人结肠癌细胞H116或者CX1细胞株[9]。化合物asperic acid(4)是从另外1株黑曲霉A. niger 94-1212的次生代谢产物中分离得到[10]。花斑曲霉A. versicolor (Vuill) Triab代谢产生六元色酮的衍生物aspergiones A-F(5-10)[11]以及aspergillone(11)、aspergillodiol(12)、aspergillol(13)和12-acetyl-aspergillol(14)[12]。3个含氯的抗生素15-17来自孔曲霉A. ostianus TUF 01F313，均对大西洋鲁杰氏菌Ruegeria atlantica有抑制活性，其中化合物16和17在25 μg/disc浓度下的抑菌圈直径分别为10.1 mm和10.5 mm，而化合物15在5 μg/disc时即表现出较好的抑制活性(抑菌圈直径为12.7 mm)，另外该化合物还有微弱的金黄色葡萄球菌抑制活性(25 μg/disc时抑菌圈直径为10.2 mm)[13]。进一步研究还分离到aspinotriols A(18)和B(19)、aspinonediol(20)[14]，aspergillides A-C(22-24)[15]及其七环生物碱化合物21-hydroxystephacidin A(25)[16](图 1)。并确定了dihydroaspyrone(21)的绝对构型[14]，其中化合物22-24对L1210细胞的LD50分别为2.1、71.0和2.0 μg/mL[15]。
图1 化合物1–92的结构 Figure 1. Structures of compounds 1–92.
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Circumdatins D-F(26-28)分离自另外一株孔曲霉A. ostianus IBT 12704[17]。混源萜tropolactones A-D(29-32)由曲霉属Aspergillus sp. CNK-371代谢产生，其中化合物29-31对HCT-116细胞有微弱的抑制活性，IC50分别为 13.2、10.9 和13.9 μg/mL[18]。棘孢曲霉A. aculeatus CRI323-04代谢产生aspergillusol A(33)[19]和asperaculin A(34)[20]，其中化合物33对酵母和嗜热脂肪芽孢杆菌来源的α-糖苷酶有抑制活性，IC50值分别为465和1060 μmol/L[19]。化合物35-37来自另一株棘孢曲霉A. aculeatus CRI322-03[21]。曲霉A. insuetus代谢产生Terretonins E(38)和F(39)，均具有哺乳动物线粒体呼吸链抑制作用，IC50值分别为3.90和2.97 μmol/L[22]。菌核曲霉A. sclerotiorum Huber SP080903f04代谢产生N-去甲棕曲菌素JBIR-15(40)[23]。焦曲霉A. ustus 8009代谢产生7个补身烷倍半萜化合物41-47，其中44、45对多种肿瘤细胞有细胞毒活性，尤其是45对L5178Y细胞株的EC50值为0.6 μg/mL[24]。蛇孢甲壳素48-52及吡咯生物碱53、54也来自同一株菌[25]。脂肽fellutamide C(55)(图 1)来自于A. versicolor，对SK-MEL-2、XF498和HCT15的IC50分别为5.1、3.9和3.1 μmol/L[26]。
JBIR-74(56)和JBIR-75(57)来自Aspergillus sp. fs14[27]。混源萜insuetolides A-C(58-60)和补身烷倍半萜61来自奇突曲霉A. insuetus OY-207，其中化合物58有抑制粗糙链孢霉菌的活性、MIC为140 μmol/L，化合物60和61对人MOLT-4细胞有细胞毒活性、50 mg/mL时的抑制率分别为51%和55%[28]。脂肽fellutamide F(62)来自A. versicolor PF10M，对多株人癌细胞的EC50为0.13-1.81 μg/mL[29]。Aspergillus sp.代谢产生4个没药烷倍半萜aspergiterpenoid A(63)、(-)-sydonol(64)、(-)-sydonic acid(65)和化合物66，其对金黄色葡萄球菌、枯草芽孢杆菌、蜡状芽孢杆菌等有抑菌活性(MIC为1.25-20.0 μmol/L)[30]。没药烷倍半萜二聚体disydonols A-C(67-69)也来自同一株菌，其中化合物67和69对HepG-2和Cashi细胞均有细胞毒活性(IC50分别为9.31/12.40 μg/mL和2.91/10.20 μg/mL)[31]。缩酚酸环醚70-72、二芳基醚73及吡喃酮74来自爪甲曲霉A. unguis CRI282-03，其中化合物70-72均有芳香酶抑制活性(IC50分别为2.2、4.1和0.7 μmol/L)，且70和71在黄嘌呤氧化测试中表现出自由基清除活性(IC50分别为16.0和<15.6 μmol/L)[32]。二酮哌嗪二聚体eurocristatine(75)产自冠突散囊菌Eurotium cristatum KUFC 7356[33]，E. cristatum是小冠曲霉A. cristatellus的有性型。1株Aspergillus sp.代谢产生austalides M-Q(76-80)[34]、tryptoquivaline K (81)和 fumiquinazolines K-P (82-87)[35]以及生物碱88和混源萜austalide R(89)[36] (图 1)。其中化合物81在10 μg/mL浓度下对小鼠淋巴瘤细胞L5178Y的抑制率为23%[35]，化合物88能选择性抑制弧菌(Vibrio sp.)生长，而89则广谱抗菌、其对Vibrioharveyi、V. proteolyticus、V. carchariae、Shewanella putrefaciens、Roseobacter litoralis、Pseudoalteromonas elyakovii、P. irgensii和Halomonas aquamarina均有抑制作用[36]。
杂色曲霉A. versicolor MF359代谢产生3个柄曲霉素90-92(图 1)，其中化合物92对金黄色葡萄球菌和枯草芽孢杆菌均有抑制活性，MIC分别为12.500 μg/mL和3.125 μg/mL[37]。黑曲霉A. niger代谢产生3,3-bicoumarin bicoumanigrin(93)、aspernigrins A和B(94、95)以及pyranonigrins A-D(96-99)(图 2)；化合物93在浓度1-20 μg/mL时具有人肿瘤细胞毒活性，化合物94、95在浓度为50 μg/mL有轻微的肿瘤细胞毒活性；化合物95具有神经保护作用[38]。Nafuredin(100)产自黑曲霉Aspergillus niger FT-0554，表现出猪蛔虫Ascarissuum延胡索酸还原酶(NFRD)抑制活性，其IC50为12 nmol/L[39]。
图2 化合物93–173的结构 Figure 2. Structures of compounds 93–173.
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1.2 珊瑚来源的曲霉天然产物土曲霉A. terreusHKI0499代谢产生aspernolides A、B(101、102)[40]。(+)-methyl sydowate(103)、7-deoxy-7,14-didehydrosydonic acid(104)和7-deoxy-7,8-didehydrosydonic acid(105)(图 2)来自一株Aspergillus sp.，其中化合物103可抑制金黄色葡萄球菌、100 μg/mL浓度下抑菌圈直径为11 mm[41]。Aspergilones A、B(106、107)来自同一株菌，其中化合物106对HL-60、MCF-7和A549细胞的IC50分别为3.2、25.0和27.0 μg/mL，且有抗污损作用、EC50为7.7 μg/mL[42]。A. sydowii PSU-F154代谢产生倍半萜aspergillusenes A (108)、B (109)和methylsydonic acid (110)，以及氧杂蒽酮aspergillusones A(111)和B(112)[43]。A. versicolor LCJ-5-4代谢产生环五肽versicoloritides A-C(113-115)、地衣酚四聚体tetraorcinol A(116)、内酯versicolactones A、B(117、118)[44]以及喹唑啉酮生物碱cottoquinazolines B-D(119-121)[45]，其中化合物116有弱的DPPH自由基清除活性(IC50为67 μmol/L)，化合物121对白色念珠菌有中等抑菌活性(MIC 22.6 μmol/L)；化合物116[46]、121[47]被NPR选为热点化合物；经过全合成研究，化合物versicolactones A和B的结构分别修正为122和123[48]。烟曲霉A. fumigates代谢产生新吲哚生物碱124和125[49]。二酮哌嗪生物碱spirotryprostatin F(126)[50]和fumiquinazoline K(127)以及萜类化合物128[51]来自另一株烟曲霉A. fumigatus KMM 4631，其中化合物126在较低浓度(0.1-1.0 μmol/L)时可以促进大豆、荞麦和小麦发芽[50]。吲哚生物碱cyclotryprostatin E(129)来自萨氏曲霉A. sydowii SCSIO 00305[52]。内生曲霉Aspergillus sp.代谢产生二倍半萜ophiobolin O(130)和6-epi-ophiobolin O(131)，对P388均有较强的细胞毒活性，IC50分别为4.7和9.3 μmol/L[53]，且化合物130可以使MCF-7周期停滞于G0/G1期(IC50为17.86 μmol/L)、并通过MAPK途径使MCF-7呈现时间和剂量依赖的细胞凋亡[54]。土曲霉菌A. terreus SCSGAF0162代谢产生asperterrestide A(132)、terremide C(133)和aspernolide E(134)(图 2)，化合物132对组织细胞淋巴瘤细胞U937和急性淋巴母细胞白血病细胞MOLT-4的IC50值分别是6.4和6.2 μmol/L，对流感病毒H1N1和H3N2的IC50值分别是15.0 μmol/L和8.1 μmol/L[55]。
曲霉菌Aspergillus sp. XS-20090066代谢产生吲哚生物碱17-epi-notoamidesQ、M(135、136)和苯醚衍生物cordyols D、E(137、138)[56]。曲霉菌A. elegansZJ-2008010代谢产生4′-OMe-asperphenamate(139)和细胞松弛素aspochalasins A1和Z24(140、141)，其中化合物139对表皮葡萄球菌S. epidermidis表现出了选择性的抑制活性(MIC值为10 μmol/L)[57]。曲霉菌Aspergillus sp. SCSGAF 0076代谢产生了大环内酯aspergillide D(142)[58]。赤散囊菌Eurotium rubrum SH-823代谢产生硫代物eurothiocins A和B(143和144)，抑制α-糖苷酶的IC50值分别为17.1 μmol/L和42.6 μmol/L[59]。杂色曲霉A. versicolor代谢产生核苷类化合物145和146，对表皮葡萄球菌有选择性抑制作用、MIC值为12.5 μmol/L，对卤虫有致死活性，LC50值为8.4 μg/mL[60]。曲霉菌A. flavipes代谢产生脑苷脂flavicerebrosides A和B(147和148)(图 2)，均对KB细胞有细胞毒活性，IC50值分别为20.7 μg/mL和14.3 μg/mL[61]。
1.3 其它动物来源的曲霉天然产物Fumiquinazolines A-C(149-151)来自烟曲霉A. fumigatus OUPS-T106B-5，有中等细胞毒活性[2](Numata et al. 1992)，其结构通过全合成确证[62, 63]；该菌株还产生fumiquinazolines D-G(152-155)[64]、cephalimysin A(156)[65]及cephalimysins B-D(157-159)[66]，其中化合物149、150及152-155对P388细胞有细胞毒活性，ED50分别为6.1、16.0、13.5、13.8、14.6和17.7 μg/mL[64]，化合物156对P388和HL-60细胞的IC50值分别为15.0 nmol/L和9.5 nmol/L[65]，化合物158和159对HL-60的IC50分别为58.4和48.7 μmol/L[66]。曲霉A. terreus OUCMDZ-1925代谢产生rubrolides R(160)和S(161)，抑制K562细胞的IC50分别为12.8和10.9 μmol/L，化合物161还具有抗H1N1病毒的活性、IC50为87.1 μmol/L，化合物160具有ABTS和DPPH自由基清除活性，IC50分别为1.33 mmol/L和43.4 μmol/L[67]。曲霉Aspergillus sp. MF275代谢产生himeic acids A-C(162-164)[68]和himeic acids E-G(165-167)[69] (图 2)，其中化合物162具有泛素激活酶E1抑制活性，50 μmol/L时的抑制率为65%[68]。
曲霉Aspergillus sp. MF297-2代谢产生notoamides A-D(168-171)(图 2)，化合物168-170对Hela及L1210细胞的IC50值为22-52 μg/mL[70]；该菌株还代谢产生notoamides F-K(172-177)(图 3)，其中175对Hela有弱活性、IC50为21 μg/mL[71]。随后，又从该菌株的代谢产物中相继分离鉴定了notoamide E(178)和notoamides E2-E4(179-181)[72]、(-)-versicolamide B(182)和notoamides L-N(183-185)[73]、notoamides O-R(186-189)[74]以及notoamide S(190)[75]。具有倍半萜母核的吡啶生物碱pileotin A(191)则来自烟曲霉A. fumigatus OUPS-N138[76]。变色曲霉A. versicolor OUPS-N136代谢产生吲哚二萜anthcolorins A-F(192-197)(图 3)，其中193-195对P388细胞的IC50值在2.2-8.5 μmol/L之间[77]。
图3 化合物174–251的结构 Figure 3. Structures of compounds 174–251.
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Spiculisporic acids B-D(198-200)来自内生曲霉Aspergillus sp. HDf2[78]。环肽clavatustides A、B(201、202)[79]和C(203)[80]来自1株棒曲霉A. clavatus C2WU，其中201和202呈现剂量依赖的肝癌细胞系(HCC)增殖抑制活性。此外，201、202还可将人肝癌细胞HepG-2的细胞周期阻滞在G1期[79]。化合物204、spirotryprostatins C-E(205-207)、fumitremorgin B的衍生物(208、209)和13-oxoverruculogen(210)来自一株烟曲霉 A. fumigatus，均有细胞毒活性，尤其是化合物207对MOLT-4、HL-60和A549细胞的IC50分别为3.1、2.3、3.1 μmol/L，208对HL-60、BEL-7402细胞的IC50分别为3.4、7.0 μmol/L，209和210对HL-60细胞的IC50分别为5.4 μmol/L和1.9 μmol/L[81]。另一株烟曲霉A. fumigatus WFZ-25代谢产生螺内酰胺pseurotins A1和A2(211和212)[82]。Yanuthones A-E(A213-A217)、1-hydroxyyanuthones A、C(218、219)及22-deacetylyanuthone A(220)(图 3)产自黑曲霉A. niger F97S11[83]。
曲霉菌Aspergillus sp. MF297代谢产生多聚乙酰aspermytin A(221)，在50 μmol/L时221可诱导小鼠嗜铬细胞瘤PC-12细胞神经轴突生长[84]。黄曲霉A. flavus OUCMDZ-2205代谢产生吲哚二萜222、223和异香豆素224，其中化合物222对金黄色葡萄菌的MIC值为20.5 μmol/L，在10 μmol/L时222和223可将A549细胞阻滞在S期，化合物222对PKC-β的IC50值为15.6 μmol/L[85]。柄曲霉A. flavipes Z-4代谢产生环肽225[86](图 3)。
2 植物来源的曲霉天然产物2.1 海藻来源的曲霉天然产物Tetrahydrobostrycin(226)和1-deoxytetrahydrobostrycin(227)来自曲霉Aspergillus sp. 05F16[87]。倍半萜insulicolide A(228)来自胰岛曲霉A. insulicola[88]。杂色曲霉A. versicolor CNC 327代谢产生化合物229-232(图 3)，其中229表现出较强细胞毒活性，对HCC-2998、HCT-116、BT-549和SNB-75细胞的LC50分别为0.53、0.44、0.27和0.44 μg/mL，其对5株肾肿瘤细胞(786-0、ACHN、CAK-1、TK-10和UO-31)表现出选择性抑制活性、LC50约为0.47-0.57 μg/mL[89]。曲霉Aspergillu sp.代谢产生mactanamide(233)，具有抑制白色念珠菌活性[90]。Parasitenone(234)来自一株曲霉A. parasiticus MFA153[91]。手性双吡咯并蒽terreusinone(235)产自土曲霉A. terreus MFA 460，具有防护紫外线A的活性，ED50值为70 μmol/L[92]。曲霉菌Aspergillus sp. MFA 212代谢产生二酮哌嗪golmaenone(236)，具有防护紫外线A的活性(ED50值为90 μmol/L)和DPPH自由基清除活性，IC50值为20 μmol/L[93]。Sydowins A、B(237、238)来自萨氏曲霉A. sydowii[94]。从曲霉Aspergillus sp. MFB024的代谢产物中发现1个多氧萘氢衍生物239(chlorofusarielin B)，其对金黄色葡萄球菌、甲氧西林耐药葡萄球菌、多药耐药葡萄球菌具有一定的抑制作用，其MIC均为62.5 μg/mL [95]。Nigerasperones A-C(240-242)为黑曲霉A. niger EN-13的产物，化合物242对白色念珠菌的抑菌圈为9 mm(两性霉素的抑菌圈为12 mm)、对DPPH自由基的清除率为41.6%[96]。此菌还代谢产生asperamides A和B(243和244)[97]、ergosterimide(245)[98]、246[99]、isopyrophen(247)和aspergillusol(248)[100]，其中化合物243对白色念珠菌的抑菌圈为12 mm[97]。
化合物249、250[101]和iso-α-CPA(251)(图 3)[102]产自黄曲霉A. ?avusc-f-3，化合物251对A549细胞的IC50值为42.2 μmol/L[102]。赭曲霉A. ochraceus EN-31代谢产生2-hydroxycircumdatin C(252)[103]、7-nor-ergosterolide(253)和化合物254、255[104](图 4)，化合物252具有明显的DPPH自由基清除作用，其IC50值为9.9 μmol/L[103]。吲哚二萜asporyzin A-C(256-258)[105]和甾类asporyergosterol(259)[106]来自米曲霉A. oryzaercf-2，其中化合物A258有较强的大肠杆菌抑制作用(每孔30 μg给药时，抑菌圈为8 mm)[105]。JBIR-81(260)和JBIR-82(261)来自曲霉Aspergillus sp. SpD081030G1f1，是有效的自由基清除剂(对N18-RE-105细胞的L-谷氨酸毒性的EC50分别为0.7和1.5 μmol/L，强于对照组的8.8 μmol/L)[107]。脑苷脂类flavusides A(262)和B(263)来自黄曲霉A. flavus，抑制金黄色葡萄球菌的MIC为15.6 μg/mL，对MRSA的MIC约为31.2 μg/mL[108]。脂肪酸264和甾体265来自另一株黄曲霉A. flavus cf-5[109]。肉色曲霉A. carneus KMM4638代谢产生吲哚生物碱carneamides A-C(266-268)、喹唑酮生物碱carnequinazolines A-C(269-271)、芳基糖苷carnemycins A、B(272、273)及倍半萜274[110]。喹唑啉酮衍生物275、276和二苯醚衍生物277也来自该菌[111]。二萜asperolides A-C(278-280)[112]、wentiquinone C(281)和282[113] (图 4)来自温特曲霉A. wentii EN-48，其中化合物278和279对多种肿瘤细胞有弱的细胞毒活性(IC50为35-97 μmol/L)、化合物282有明显的DPPH自由基清除活性(IC50为5.2 μg/mL)。
图4 化合物252–331的结构 Figure 4. Structures of compounds 252–331.
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化合物283来自一株变色曲霉A. versicolor，对枯草芽孢杆菌、蜡状芽孢杆菌和金黄色葡萄球菌有中等强度的抑菌活性(每孔100 μg给药时的抑菌圈分别为11、12和14 mm)[114]。萜类化合物1,2-dihydroterretonin F(284)、(6α)-21-deoxyophiobolin G(285)、(6α)-16,17-dihydro-21-deoxyophiobolin G(286)、ophiobolin U(287)、ophiobolin V(288)、ophiobolinW(289)和290、291(图 4)来自焦曲霉A. ustus cf42，其中化合物287对大肠杆菌和金黄色葡萄球菌均有抑菌活性、每孔30 μg给药时的抑菌圈分别为15和10 mm[115]。Asperversin A(292)和293产自变色曲霉A. versicolor pt20[116]。花斑曲霉A. versicolor dl29代谢产生倍半萜albican-11,14-diol(294)[117]和生物碱aspeverin(295)[118]，其中化合物294对卤虫的LC50为35.0 μg/mL，且为大肠杆菌和金黄色葡萄球菌的抑制剂、30 μg/孔时的抑菌圈分别为7和10.3 mm[117]，而化合物295对赤潮异弯藻Heterosigma akashiwo的EC50值分别为6.3 μg/mL(24h)和3.4 μg/mL(96h)[118]。蒽醌6,8-di-O-methylaverantin(296)来自变色曲霉A. versicolor EN-7[119]。蜡叶散囊菌E. herbariorum HT-2代谢产生了吲哚二酮哌嗪二聚体cristatumin E(297)，其对K562细胞的IC50值为8.3 μmol/L，对产气杆菌Enterobacter aerogenes和大肠杆菌Escherichia coli的MIC值分别为44.0和44.0 μmol/L[120]。赭曲霉A. ochraceus Jcma1F17代谢产生倍半萜6β,9α-dihydroxy-14-p-nitrobenzoylcinnamolide(298)，对10种人体肿瘤细胞(H1975、U937、K562、BGC-823、Molt-4、MCF-7、A549、Hela、HL60和Huh-7)的IC50为1.95-6.12 μmol/L，对H3N2病毒和EV71病毒的IC50分别为17.0和9.4 μmol/L[121]。2株曲霉菌Aspergillus sp. BM-05和BM-05ML共培养产生环三肽psychrophilin E(299)(图 4)，对HCT-116细胞的IC50值为28.5 μmol/L[122]。曲霉菌A. pseudodeflectus代谢产生pseudodeflectusin(300)，对NUGC-3、HeLA-S3和HL-60均有细胞毒活性，其中对HL-60细胞的IC50值为39 μmol/L[123]。
1997年，Fenical等从曲霉Aspergillus sp. CNC139的代谢产物中分离得到二酮哌嗪类halimide(301)，其对HCT116和A2780细胞有较强的细胞毒活性，IC50分别为1 μmol/L和0.8 μmol/L[3, 4]。同时Kanoh等也从焦曲霉A. ustus NSC-F038的代谢产物中分离得到，将其命名为phenylahistin，并发现(-)-phenylahistin(302)才是真正的活性成分，对P388的IC50为0.35 μmol/L，而且1 μmol/L时可以将该细胞阻滞在G2/M期[124]，良好的生物活性使其成为先导结构。之后多个课题组通过全合成出[125, 126]，构效关系研究筛选出plinabulin(NPI-2358)(303)[5]，作为肿瘤细胞的血管分裂剂进入了Ⅱ期临床研究[127, 128, 129]。目前，plinabulin已经结束其II期临床研究，并于2015年第三季度开始在美国和中国进行其III期临床研究，用于治疗转移性的晚期非小细胞肺癌[6]。Gerwick所列的20个海洋药物中(包括7个上市药和13个临床药物)，303是唯一的海洋曲霉属真菌来源的药物[7]。近期，Hayashi小组对plinabulin进行结构改造得到活性更好的化合物KPU-300(304)(图 4)，304对HT-29细胞的IC50为7.0 nmol/L，可以有效的与微管蛋白结合(Kd = 1.3 μmol/L)，诱导微管解聚[130]。
2.2 红树林来源的曲霉天然产物黑曲霉A. niger LL-LV3020代谢产生pyranonigrin A(305)[131]。黄柄曲霉A. favipes代谢产生cytochalasins Z16-Z20(306-310)[132]。赤散囊菌Eurotium rubrum QEN-0407-G2代谢产生蒽酮衍生物eurorubrin(311)和312-314，其中化合物311显示了中等强度的DPPH自由基清除活性，IC50值为44.0 μmol/L[133]。苯并-γ-吡喃酮二聚体rubasperones A-C (315-317)[134]和rubasperones D-E(318-321)[135]分离自塔宾曲霉A. tubingensis GX1-5E。Nigerapyrones A-H(322-329)和已知物asnipyrones A和B来自黑曲霉A. niger MA132，其中已知化合物asnipyrones A和B的结构分别被修正为330和331(图 4)；化合物323对HepG2细胞的IC50为62 μmol/L，326对SW1990、DMA-MB-231和A549细胞的IC50分别为38、48和43 μmol/L[136]。单萜acetoxydehydroaustin B(332)和1,2-dihydroacetoxydehydroaustin B(333)(图 5)来自Aspergillus sp. 085241B[137]。黄曲霉A. flavus 092008代谢产生黄曲霉毒素aflatoxin B2b(334)，其对大肠杆菌、枯草芽孢杆菌和产气杆菌有中等的抑菌活性(MIC分别为22.5、1.7和1.1 μmol/L)，对A549、K562和L-02细胞的IC50分别为8.1、2.0和4.2 μmol/L[138]。Aspergillumarins A(335)和B(336)产自曲霉Aspergillus sp.，在50 μg/mL时对金黄色葡萄球菌和芽孢杆菌有抑制活性[139]。
图5 化合物332–423的结构 Figure 5. Structures of compounds 332–423.
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构巢曲霉A. nidulans MA-143代谢产生aniduqui-nolones A-C(337-339)、6-deoxyaflaquinolone E(340)、isoaflaquinolone E(341)、14-hydroxyaflaquinolone F(342)和已知物aflaquinolone A(343)(图 5)；化合物338、339和343具有抗卤虫活性，LD50值分别是7.1、4.5和5.5 μmol/L[140]。喹唑啉酮生物碱aniquinazolines A-D(344-347)也产自该菌，对卤虫的LD50分别为1.27、2.11、4.95 和 3.42 μmol/L[141]。黄柄曲霉A. flavipes AIL8代谢产生flavipesins A(348)和B(349)，348对金黄色葡萄球菌和枯草芽孢杆菌的MIC分别为8.0 μg/mL和0.25 μg/mL[142]。二倍半萜asperterpenols A(350)和B(351)来自一株内生曲霉Aspergillus sp. 085242，二者对乙酰胆碱酯酶的IC50值分别为2.3和3.0 μmol/L[143]。曲霉菌Aspergillus sp. 16-5c代谢产生二倍半萜asperterpenoid A(352)(图 5)，它对分枝杆菌Mycobacteriumtuberculosis蛋白酪氨酸磷酸酶的IC50值为2.2 μmol/L[144]。土曲霉A. terreus GX7-3B代谢产生了噻吩骈萘醌衍生物353[145]。
2.3 其它植物来源的曲霉天然产物吲哚单萜speradine A(354)产自溜曲霉A. tamarii M143，抑制Ca2+-ATP酶的IC50为8 μmol/L、抑制组蛋白去乙酰化酶的IC50为100 μg/mL，抑制藤黄微球菌Mycrococcus luteus的MIC 16.7 μg/mL[146]。6-methoxyspirotryprostatin B(355)、18-oxotryprostatin A(356)、14-hydroxyterezine D(357)、14-norpseurotin A(358)和359(图 5)来自萨氏曲霉A. sydowi PFW1-13，其中化合物355-357对A549细胞的IC50分别为8.29、1.28和7.31 μmol/L，化合物358和359对大肠杆菌、枯草杆菌和溶壁微球菌的MIC分别为3.74、14.97、7.49 μmol/L和10.65、5.33、10.65 μmol/L[147]。
3 海泥、海水等来源的曲霉天然产物3.1 海泥来源的曲霉天然产物肉色曲霉A. carneusMST-MF156代谢产生aspergillicins A-E(360-364)(图 5)，对捻转血矛线虫Haemonchus contortus具有细胞毒性(LD99为25-50 μg/mL)[148]。糖苷类化合物365产自变异曲霉A. varians KMM 4630，其在10.0 μg/mL时对海胆胚胎有毒性[149]。2,3-dimethoxyosoate(366)产自曲霉Aspergillus sp. B-F-2，其对K562细胞的IC50为76.5 μmol/L，在100 μmol/L时可以诱导细胞凋亡、使细胞停滞在S期[150]。烟曲霉A. fumigates 030402d代谢产生11-O-methylpseurotin A(367)，对Hof1 缺失的酵母菌Saccharomyces cerevisiae 的抑菌圈直径为9 mm[151]。白曲霉A. candidus RF-5672代谢产生terprenin(368)、3-methoxyterprenin(369)和4"-deoxyterpren(370)，其抑制CoA-A 介导的小鼠脾淋巴细胞的IC50依次为1.2、2.0和5.6 ng/mL，抑制LPS介导的小鼠脾淋巴细胞的IC50分别为4.5、8.0、15.6 ng/mL[152]。炭黑曲霉A. carbonarius WZ-4-11代谢产生carbonarones A (371)和B(372)[153]及化合物373-374[154]，其中371和372对K562细胞的IC50值分别为56.0和27.8 μg/mL[153]，373和374对结核分歧杆菌Mycobacterium tuberculosis H37Rv的MIC依次为43.0和25.1 μmol/L[154]。烟曲霉A. fumigates Fres代谢产生胶霉素375[155]和二酮哌嗪376-378[156]。变色曲霉A. versicolor MST-MF495代谢产生cottoquinazoline A(379)和cotteslosins A(380)和B(381)[157]。氧杂螺内酰胺azaspirofurans A(382)和B(383)来自萨氏曲霉A. sydowi D2-6，382对A549的IC50 10 μmol/L[158]。二酮哌嗪azonazine(384)来自胰岛曲霉A. insulicola 088708a，有抗炎作用，其对NF-κB的IC50为8.37 μmol/L[159]。杂萜asperdemin(385)来自变色曲霉A. versicolor，有溶血作用，EC50 1.15 mmol/L[160]。环肽unguisin E(386)和deoxyapoaranotin(387)分别来自曲霉Aspergillus sp. AF119[161]和变色曲霉A. versicolor KMD 901[162]，Aspergillus sp. AF119还代谢产生barceloneic lactones B(388)和C(389)和5'-hydroxychlorflavonin(390)[163]以及terphyl acid(391)、terphyl diacid(392)[164](图 5)。
Protulactones A、B(393、394)[165]及protuboxepins A、B(395、396)、protubonines A、B(397、398)(图 5)来自Aspergillus sp. SF-5044[166]，该菌还代谢产生aflaquinolones A-G(399-405)[167]。A. versicolor ZLN-60产生环戊肽versicotides A(406)、B(407)[168]和异戊二烯化的二苯醚衍生物diorcinols B-E(408-411)[169]，其中化合物410对Hela和K562细胞的IC50值分别为 31.5 和 48.9 μmol/L、411对Hela细胞的IC50值为36.5 μmol/L[169]。台中曲霉A. taichungensis ZHN-7-07代谢产生prenylterphenyllins A-C(412-414)、4''-dehydro-3-hydroxyterphenyllin(415)及prenylcandidusins A-C(416-418)，其中化合物412对HL-60和A549细胞的IC50分别为1.5和8.3 μmol/L、415和417对P388细胞的IC50分别为2.7和1.6 μmol/L[170]。补身烷倍半萜419-423(图 5)来自一株焦曲霉A. ustus，化合物422抑制P388的IC50为8.7 μmol/L[171]。Prenylcyclotryprostatin B(424)、20-hydroxycyclotryprostatin B(425)、9-hydroxyfumitremorgin C(426)、6-hydroxytryprostatin B(427)和spirogliotoxin(428)(图 6)来自烟曲霉A. fumigates YK-7，化合物424和426对U937细胞的IC50分别为25.3 μmol/L和18.2 μmol/L[172]。土曲霉A. terreus A8-4代谢产生7''-hydroxybutyrolactone III(429)和terretriones A-C(430-432)[173]；三肽presclerotiotide F(433)来自胰岛曲霉A. insulicola 088708aZA[174]；萘烷衍生物decumbenone C(434)来自硫色曲霉A. sulphureus KMM 4640，对人体黑色素瘤SK-MEL-5的细胞毒活性IC50为0.9 μmol/L[175]。二酮哌嗪brevianamides S-V(435-438)来自变色曲霉A. versicolor MF030，化合物435具有选择性地抑制结核分支杆菌Mycobacterium bovis减毒株BCG的活性(MIC为6.25 μg/mL)，可能发展为抗结核杆菌先导药物[176]。焦曲霉A. ustus 094102代谢产生倍半萜ustusols A-C(439-441)和ustusolates A-E(442-446)以及香豆素ustusoranes A-F(447-452)，其中446和451对HL-60的IC50值分别为9.00 μmol/L和0.13 μmol/L，444对A549细胞的IC50为10.5 μmol/L[177]。外消旋的螺环生物碱effusin A(453)和dihydrocryptoechinulin D(454)(图 6)分离自赭曲霉A. effuses H1-1[178, 179]，其中454对P388和HL-60细胞的IC50分别为1.83 μmol/L和4.80 μmol/L、在100 μmol/L时可以选择性的抑制拓扑异构酶I的活性[178].
图6 化合物424–517的结构 Figure 6. Structures of compounds 424–517.
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曲霉A. westerdijkiae DFFSCS013代谢生物碱circumdatins K(455)和L(456)、5-chlorosclerotiamide(457)、10-epi-sclerotiamide(458)和aspergilliamide B(459)(图 6)，其中化合物457和458对K562细胞的IC50值分别是44和53 μmol/L[180]。三聚的sydowiols A-C(460-462)产自一株萨氏曲霉A. sydowii MF357，化合物460和462对结核分枝杆菌M. tuberculosis蛋白酪氨酸磷酸酶PtpA的IC50值分别为14 μg/mL和24 μg/mL。此外，化合物462对金黄色葡萄球菌的MIC值为12.5 μg/mL[181]。棘孢曲霉A. aculeatus代谢产生新苯醌aculeatusquinones A-D(463-466)，其中464和466对HL-60、K562和A549细胞的IC50值在5.4-76.1 μmol/L之间[182]。杂色曲霉A. versicolor HDN08-60代谢产生吲哚二酮哌嗪versicamides A-H(467-474)；其中474对Hela、HCT-116、HL-60和K562细胞的IC50分别为19.4、17.7、8.7 和22.4 μmol/L，474也可抑制多种酪氨酸激酶的活性，10 μmol/L对KDR、RET和EGFR激酶的抑制率为23%到35%，对c-Kit的抑制率为60%[183]。米曲霉A. oryzae代谢产生吲哚生物碱speradines B-E(475-478)，475和478对Hela细胞的IC50均为0.20 mmol/L[184]；吲哚生物碱speradines F-H(479-481)和circumdatin G(482)分别来自米曲霉A. oryzae[185]和褐黄曲霉A. ochraceus[186]。灰绿曲霉A. glaucus HB1-19代谢产生aspergentisyls A、B(483、484)和aspergiodiquinone(485)(图 6)，483和484具有DPPH自由基清除活性，IC50值分别为9.3 μmol/L和17.6 μmol/L[187]。蒽醌类衍生物aspergiolide A(486)产自同一株菌，对A549、HL-60、BEL-7402有细胞毒活性[188]。
菌核曲霉A. sclerotiorum PT06-1在高盐寡营养条件下产生环六肽sclerotides A、B(487、488)[189]，在高盐富营养条件下则产生环三肽sclerotiotides A-K(489-499)[190]和indole-3-ethenamide(500)[191]；其中化合物487和488均显示中等强度的抗白色念珠菌活性、MIC值分别为7.0 μmol/L和3.5 μmol/L，化合物488对HL-60细胞和铜绿假单胞菌有抑制作用、IC50和MIC值分别为56.1和35.3 μmol/L；化合物489、490、494和497对白色念珠菌有选择性抑制作用，MIC分别为7.5、3.8、30.0和6.7 μmol/L，化合物500对A549和HL-60细胞的IC50分别为3.0和27.0 μmol/L。土曲霉A. terreus PT06-2在盐胁迫条件下代谢产生terremides A、B(501-502)和terrelactone A(503)，其中501对金黄色葡萄球菌的MIC为63.9 μmol/L、502对产气肠杆菌的MIC为33.5 μmol/L[192]。烟曲霉A. fumigates BM939代谢产生对映异构的tryprostatins A(504)和B(505)(图 6)，浓度分别为50 μg/mL和12.5 μg/mL时，两者均能将tsFT-210的细胞周期阻滞于G2/M期[193]。
3.2 海水来源的曲霉天然产物Asperiamide A(506)产自曲霉Asperillus sp. MF-34[194]，asperiamides B(507)和C(508)则来自黑曲霉A. niger MF-16[195]。曲霉Aspergillussp. MF-93代谢产生asperxanthone(509)和asperbiphenyl(510)(图 6)，均可阻断烟草花叶病毒TMV的复制，0.2 mg/mL浓度下的抑制率分别为62.9%和35.5%[196]。杂色曲霉A. versicolor ZBY-3的新霉素耐药菌株u2n2h3-3代谢产生5-oxo-L-prolinate(511)，其对Hela细胞的IC50值为49.0 μg/mL[197]。柄曲菌素类oxisterigmatocystins A-C(512-514)[198]和二酮哌嗪brevianamide W(515)[199]来自变色曲霉A. versicolor CXCTD-06-6a，其中515在13.9 μmol/L时对DPPH的清除率为55%。
3.3 未知来源的曲霉天然产物二倍半萜aspergilloxide(516)和二聚二酮哌嗪517(图 6)分别来自曲霉Aspergillus sp. CNM-713[200]和黑曲霉A. niger[201]。
4 结论和展望从1992年Shinggu等首次报道海洋曲霉来源的新天然产物fumiquinazolines A-C[2](Numata et al. 1992)到2014年8月，已发现海洋曲霉来源的新天然产物512个。海洋曲霉天然产物的结构类型多样，包括聚酮、生物碱、萜类、甾体、脂肪酸、肽类及其卤代物和糖苷等；且36%的化合物表现出抗癌(肿瘤细胞毒)、抑菌、抗氧化(自由基清除)和抗寄生虫等生物活性，是发现活性新天然产物和药物先导物的重要资源。
(1) 从海洋曲霉菌的样品来源看，产生新化合物最多的曲霉菌来源或栖息地依次是海泥(149个)、海绵(100个)、其它动物(77个)和海藻(75个)，分别占29%、20%、15%和15%(图 7-A)。
图7 海洋曲霉天然产物的来源(A)与结构分类(B) Figure 7. Origin categories (A) and the main structure types (B) of marine-derived Aspergillus fungal NPs.
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(2) 从化合物类型看，化合物最多的类型依次是含氮(265个)、聚酮(153个)和萜甾(96个)，分别占化合物总数的52%、30%和19%(图 7-B)。进一步分析其来源，聚酮类化合物产生菌的主要栖息地是海泥和海绵，分别为26%和22%；萜甾化合物产生菌的主要栖息地是海绵和海藻，分别为38%和25%；含氮化合物产生菌的主要栖息地是海泥，为35% (图 8-A)。进一步结合来源分析，珊瑚、海藻和海泥来源的曲霉主要代谢产生含氮化合物，分别为48%、51%和63%；红树林来源的曲霉主要代谢产生聚酮化合物，约为64%；而海绵来源的曲霉天然产物的结构类型相对均衡，聚酮、含氮化合物及萜甾分别为33%、27%和36% (图 8-B)。
图8 主要结构类型化合物产生菌的栖息地(A)与不同样品来源的曲霉天然产物的结构类群(B) Figure 8. Habitat categories on the main structures of producing strains (A) and structural categories (B) of NPs from marine-derived Aspergillus fungi.
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(3) 约36%的海洋曲霉天然产物(184个)表现出细胞毒、抗菌、自由基清除和抗寄生虫等多种生物活性(图 9-A和表 1)，而肿瘤细胞毒(94个)和抗菌(51个)是其主要的活性，分别占活性化合物总数的51%和28%。含氮物、聚酮和萜甾是活性化合物的三大类型，分别占活性化合物总数的57%、29%和20% (图 9-B)；卤代物、含氮物、萜甾、聚酮和肽类出现活性化合物的比例分别为各类化合物总数的50%、40%、41%、38%和35% (图 10-A)；而海泥和海绵来源的曲霉最容易产生肿瘤细胞毒活性的化合物，其概率分别为21%和19% (图 10-B)。
图9 海洋曲霉天然产物的活性分类(A)与活性化合物中各结构类型的比例(B) Figure 9. Bioactive categories of NPs (A) and ratios of the bioactive NPs from structural types (B) of the marine-derived Aspergillus fungal origins.
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图10 不同结构类型化合物的活性率(A)与产生菌来源化合物的活性率(B) Figure 10. Ratios of active NPs from the structural types (A) and the sources of the Aspergillus fungi (B).
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(4) 我国、其它亚洲国家和欧美国家在海洋天然产物的发展上占据了重要地位，分别贡献287、108和103个新化合物，尤其是我国海洋天然产物化学家贡献了57%的海洋曲霉来源的新天然产物(图 11-A)。本文共引用了95篇(占引用文献总数的53%)我国海洋天然产物化学家发表的文章，是主要的贡献者，标志我国海洋天然产物的研究具有一定的国际影响力。但其发表在有机化学类或天然产物化学类的主流杂志如Org. Lett.、J. Org. Chem.、Tetrahedron和J. Nat. Prod.分别仅有6、1、2和11篇，仅占其文章的6.3%、1.1%、2.1%和11.6%，且未见其在J. Am. Chem. Soc.和Angew. Chem.,Int. Ed.等化学综合类高水平杂志上发表文章(图 11-B)，也未见有药进入临床研究。由此可见，我国曲霉菌海洋天然产物的研究，应该注重质和国家需求，而非单纯的量或发表文章。
图11 海洋曲霉天然产物发现者国别(A)和中国****发表论文的期刊分类(B) Figure 11. Country categories of the discoverers (A) and publishing Journal categories of the Chinese scholars (B) on the marine-derived fungal NPs
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综上，海洋曲霉可以产生结构新颖，活性多样的天然产物，具有极大的开发潜能，但是到目前为止仅有1个来源于海洋曲霉的药物，如何最大限度利用海洋曲霉这类珍贵的微生物资源来开发药物，是值得科研工作者思考和解决的问题。一方面要通过培养基改造、表观遗传修饰和共培养等手段，继续发现新的活性天然产物；另一方面也是最重要的，是如何开展对现有活性天然产物的成药性研究，而化合物的量依然是制约成药性研究的瓶颈因素。发酵工程、代谢工程是开展微生物活性产物规模化制备、获取足量产物的有效方法，而合成生物学为代谢工程有效而系统的分子生物学工具。由于真菌的基因组较大、酶系复杂，制约着其合成生物学的研究。近年来，曲霉次级代谢产物合成酶系及其相关基因结构、功能的研究取得了很大的进展，多个曲霉的基因组序列被公开。一些曲霉属真菌次级代谢产物的生合成机理被阐明，为曲霉属真菌活性天然产物的规模化制备和工业化生产提供了技术和理论基础。如张立新课题组发现真菌毒素verruculogen中的过氧桥键是由一个依赖α-酮戊二酸的单核非血红素酶FtmOx1催化合成的[202]。降血脂的一线药物洛伐他汀(lovastatin)最初是从曲霉中发现，目前控制洛伐他汀的生物合成酶被发现，并通过曲霉发酵实现工业化生产[203, 204]；洛伐他汀的衍生物辛伐他汀(simvastatin)也是一种有效的调血脂药物，经典的合成方法是从洛伐他汀出发，经过水解(得到关键中间体monacolin J)、保护、酰化和脱保护等多步反应得到。Yi Tang等在解析洛伐他汀生物合成中酰化酶的基础上，利用全细胞培养，在大肠杆菌(Escherichia coli)过表达酰基转移酶lovD，实现了辛伐他汀的高效合成(转化monacolin J为simvastatin的转化率达到99%以上，且产量达到克级：4?6 g/L)[205, 206]。这些研究成果为海洋曲霉属真菌药物的开发提供了重要的参考。
表1. 海洋曲霉来源天然产物(1992–2014)Table 1. Marine natural products from Aspergillus fungi (1992–2014)
CompoundsProducing StrainsEnvironments sourceBioactivityReferences
a /: no bioactivity was reported.
1, 2A. cf. ochraceus 941026Jaspis of Coriacea, Indian-Pacific Ocean/ a8
3A. nigereHyrtios sp., Florida, AmericaCytotoxicity9
4A. niger 94–1212Hyrtios proteus, Florida, America/10
5–14A. versicolor(Vuill)TriabXestospongia exigua, Bali Island, Indonesia/11–12
15–25A. ostianus TUF 01F313Unidentified sponge, Pohnpei, Micronesia15–17: Antibacterial activity,
22–24: Cytotoxicity		13–16
26–28A. ostianus IBT 12704Unidentified sponge, Pohnpei, Micronesia/17
29–32Aspergillus sp. CNK-371Unidentified sponge, Hawaii State29–31: Cytotoxicity18
33, 34A. aculeatus CRI323-04Xestospongia testudinaria, Phi Phi Island, Thailand33: α-glucosidase inhibition,
Antibacterial activity		19–20
35–37A. aculeatus CRI322-03Unidentified sponge, Phi Phi Island, Thailand/21
38, 39A. insuetusPetrosia ficiformis, Santa Ana Alhambra Nestorius, SpainInhibitor of the mammalian
mitochondrial respiratory chain		22
40A. sclerotiorum Huber SP080903f04Mycale sp. Okinawa Island, Japan/23
41–54A. ustus 8009Suberites domuncula, The Adriatic Sea44, 45: Cytotoxicity24–25
55A. versicolorPetrosia sp., Jeju Island, KoreaCytotoxicity26
56, 57Aspergillus sp. fs14Unidentified sponge, Okinawa Island, Japan/27
58–61A. insuetus OY-207Psammocinia sp., Israel58: Antibacterial activity
60: Cytotoxicity		28
62A. versicolor PF10MPetrosia sp., Jeju Island, KoreaCytotoxicity29
63–69Aspergillus sp.Xestospongia testudinaria, South China Sea, China63–66: Antibacterial activity
67, 69: Cytotoxicity		30–31
70–74A. unguis CRI282-03Unidentified sponge CRI282, Thailand70–72: Aromatase inhibition
70, 71: XXO scavenging activity		32
75Eurotium cristatum KUFC 7356Mycale sp. State Beach, Thailand/33
76–89Aspergillus sp.Tethya aurantium, Mediterranean, Italy81: Cytotoxicity
88, 89: Antibacterial activity		34–36
90–92A. versicolor MF359Hymeniacidon perleve, Bohai, China92: Antibacterial activity37
93–99A. nigerAxinella damicornis, Elba, Italy93–95: Cytotoxicity38
100Aspergillus niger FT–0554Unidentified sponge, PalauInhibit Ascarissuum39
101, 102A. terreus HKI0499Sinularia kavarattiensis, Amanda Pam, India/40
103–107Aspergillus sp.Dichotella gemmacea, Weizhou Island, China103: Antibacterial activity
106: Cytotoxicity, fouling resistance		41–42
108–112A. sydowii PSU-F154Annella sp., Surat Thani, Thailand/43
113–121A. versicolor LCJ-5-4Cladiella sp., South China Sea, China116: DPPH radical scavenging activity
121: Antibacterial activity		44–45
124, 125A. fumigatesZoanthus sp., Kagoshima, Japan/49
126–128A. fumigatus KMM 4631Sinularia sp., Ostrov Kunashir Island126: Planta growth Promotion50–51
129A. sydowii SCSIO 00305Verrucella umbraculum, Sanya, China/52
130, 131Aspergillus sp.Zoanthus sp., Kagoshima, JapanCytotoxicity53–54
132–134A. terreus SCSGAF0162Echinogorgia aurantiaca, Sanya, China132: Cytotoxicity, Antivirus55
135–138Aspergillus sp. XS-20090066Dichotella gemmacea, Xisha Islands, South China Sea/56
139–141A. elegansZJ-2008010Sarcophyton sp., Weizhou Island, China139: Antibacterial activity57
142Aspergillus sp. SCSGAF 0076Melitodes squamata, Sanya, China/58
143, 144Eurotium rubrum SH-823Sarcophyton sp., South China Sea, ChinaAnti-α-glycosides59
145, 146A. versicolorDichotella gemmacea, South China Sea, ChinaAntibacterial activity, Anti-brine shrimp activity60
147, 148A. flavipesAnthopleura xanthogrammica, Qingdao, ChinaCytotoxicity61
149–156A. fumigatus OUPS-T106B-5Pseudolabrus japonicus, Tanabe Bay, JapanCytotoxicity2, 64–65
157–159A. fumigatus OUPS-T106B-5Pseudolabrus japonicus, Tanabe Bay, Japan158, 159: Cytotoxicity66
160–161A. terreus OUCMDZ-1925Chelon haematocheilus, Yellow River estuary, ChinaDPPH radical scavenging; Cytotoxicity; Anti-virus67
162–167Aspergillus sp. MF275Mytilus edulis, Toyama Bay, Japan162: Ubiquitin-activating enzyme (E1) inhibitor68–69
168–190Aspergillus sp. MF297-2Mytilus edulis, Japan170, 175: Cytotoxicity70–75
191A. fumigatus OUPS-N138Toxopneustes pileolus, Japan/76
192–197A. versicolor OUPS-N136Anthocidaris crassispana, Tanabe Bay, Wakayama, Japan193–195: Cytotoxicity77
198–200Aspergillus sp. HDf2Anthocidaris crassispina, Hainan, China/78
201–203A. clavatus C2WUXenograpsus testudinatus, Taiwan, China201–202: Cytotoxicity79–80
204–210A. fumigatusS. japonicus, Lingshan Island, Qingdao, China207–210: Cytotoxicity81
211–212A. fumigatus WFZ-25S. japonicus, Jiaozhou Bay, China/82
213–220A. niger F97S11Aplidium sp., Fiji/83
221Aspergillus sp. MF297Mytilus edulis, Toyama Bay, JapanCytotoxicity84
222–224A. flavus OUCMDZ-2205Penaeus vannamei, Lianyungang sea area, China222: Antibacterial activity
222–223: Cytotoxicity		85
225A. flavipes Z-4Ligia oceanica, Oceania/86
226–227Aspergillus sp. 05F16Unidentified marine alga, Indonesia/87
228A. insulicolaUnidentified marine alga, Bahamas/88
229–232A. versicolor CNC 327Penicillus capitatus, Caribbean229: Cytotoxicity89
233Aspergillu sp.Sargassum sp., Philippines233: Antibacterial activity90
234A. parasiticus MFA153Carpopeltis cornea, Korea/91
235A. terreus MFA 460Halymenia acuminata, KoreaUV-A absorbing activity92
236Aspergillus sp. MFA 212Lomentaria catenata, Ulsan, KoreaUV-A absorbing activity; DPPH radical scavenging93
237–238A. sydowiiAcanthophora spicifera, Bay of Bengal India/94
239Aspergillus sp. MFB024Sargassum horneri, KoreaAntibacterial activity95
240–248A. niger EN-13Colpomenia sinuosa, Qingdao, China242: Antibacterial activity; DPPH radical scavenging
243: Antibacterial activity		96–100
249–251A. flavus c-f-3Enteromorpha tubulosa, Putian, China251: Cytotoxicity101–102
252–255A. ochraceus EN-31Sargassum kjellmanianum, Daliancoastline, China252: DPPH radical scavenging103–104
256–259A. oryzaer cf-2Heterosiphonia japonica, Yantai, China258: Antibacterial activity105–106
260–261Aspergillus sp. SpD081030G1f1Sargassum sp., Ishigaki Island, JapanDPPH radical scavenging107
262–263A. flavusCodium fragile,Yeosu, KoreaAntibacterial activity108
264–265A. flavus cf-5Corallina officinalis, Yantai, China/109
266–277A. carneus KMM4638Laminaria sachalinensis, Kunachir Island/110–111
278–282A. wentii EN-48Sargassum sp., Unknown place278–282: Cytotoxicity
282: DPPH radical scavenging		112–113
283A. versicolorHalimeda opuntia, Egyptian Red Sea (5–8 m)Antibacterial activity114
284–291A. ustus cf42Codium fragile, Zhoushan Island, China287: Antibacterial activity115
292–293A. versicolorpt20Sargassum thunbergii, Pingtan Island, China/116
294–295A. versicolor dl29Codium fragile, Dalian, China294: Anti-brine shrimp activity, Antibacterial activity
295: Inhibition of H. akashiwo		117–118
296A. versicolor EN-7Sargassum thunbergii, Qingdao, China/119
297E. herbariorum HT-2Enteromorpha prolifera, Qingdao, ChinaCytotoxicity, Antibacterial activity120
298A. ochraceus Jcma1F17Coelarthrum sp., Paracel Islands, ChinaCytotoxicity, Anti- H3N2 and EV71 activity121
299Aspergillus sp. BM-05 and BM-05MLSargassum sp., Helgoland, North Sea, GermanyCytotoxicity122
300A. pseudodeflectusSargassum fusiform, Miura Peninsula, JapanCytotoxicity123
301Aspergillus sp. CNC139
A. ustus NSC-F038		Halimeda copiosa, PhilippinesCytotoxicity3, 4
305A. niger LL-LV3020Mangrove wood, Hong Kong, China/131
306–310A. favipesMangrove Plant Acanthus ilicifolius, Dongzhai Gang, China132
311–314Eurotium rubrum
QEN-0407-G2		Marine mangrove plant Hibiscus tiliaceus, Hainan Island, China311: DPPH radical scavenging133
315–321A. tubingensis GX1-5ERadix of Pongamia pinnata, South China Sea, Guangxi/134–135
322–331A. niger MA132Mangrove, Hainan, China323, 326: Cytotoxicity136
332–333Aspergillus sp. 085241BMangrove, Shankou, Guangxi, China/137
334A. flavus 092008Mangrove plant, Hainan, ChinaCytotoxicity, Antibacterial activity138
335–336Aspergillus sp.Bruguiera gymnorrhiza, South China Sea, China/139
337–347A. nidulans MA-143Rhizophora stylosa, Unknown place338–339, 343, 344–347: Anti-brine shrimp activity140–141
348–349A. flavipes AIL8Acanthus ilicifolius, Daya Bay, Shenzhen, ChinaAntibacterial activity142
350–351Aspergillus sp. 085242Mangrove plant, Guangxi, ChinaAcetylcholinesterase inhibition143
352Aspergillus sp. 16-5cMangrove plant, South China Sea, ChinamPTPB inhibition144
353A. terreus GX7-3BBruguiera gymnoihiza, Guangxi, China/145
354A. tamarii M143Driftwood, Okinawa Island, IapanCa2+-ATPase inhibition, Antibacterial activity146
355–359A. sydowi PFW1-13Driftwood, Baishamen,Hainan, ChinaCytotoxicity, Antibacterial activity147
360–364A. carneus MST-MF156Sediment, Jordan River Bridge, Tasmania, AustraliaAntiparasitic activity148
365A. varians KMM 4630Sediment, Sakhalin IslandCytotoxicity149
366Aspergillus sp. B-F-2Sediment, Behai Bay, ChinaCytotoxicity150
367A. fumigates 030402dSediment (>30 m), VanuatuAntimicrobial activity151
368–370A. candidus RF-5672Sediment, Shodo Island, Kagawa Prefecture, JapanCytotoxicity152
371–374A. carbonarius WZ-4-11Sediment, Weizhou Island, China371–372: Cytotoxicity;
373–374: Antimicrobial activity		153–154
375–378A. fumigates FresSediment, Jiaozhou Bay, Qingdao, China/155–156
379–381A. versicolor MST-MF495Beach sand sample, Cottesloe, Western Australia/157
382, 383A. sydowi D2–6Sediment, Jiaozhou Bay, Qingdao, China382: Cytotoxicity158
384A. insulicola 088708aSediment, HawaiiAnti-inflammation159
385A. versicolorSediment, Sakhalin Bay, RussianAntihemolysis160
386Aspergillus sp. AF119Sediment, Xiamen beach, China/161
387A. Versicolor KMD 901Sediment, East Sea, Korea/162
388–392Aspergillus sp. AF119Sediment, Xiamen beach, China/163–164
393–405Aspergillus sp. SF-5044Sediment, Dadaepo Beach, Busan, Korea/165–167
406–411A. versicolor ZLN-60Sediment, Yellow Sea410, 411: Cytotoxicity168–169
412–418A. taichungensis ZHN-7-07Root soil of the mangrove plant Acrostichum aureum412, 415, 417: Cytotoxicity170
419–423A. ustusRhizosphere soil of the mangrove Acrostichum aureurm, Guangxi, China422: Cytotoxicity171
424–428A. fumigates YK-7Sediment, Yingkou, China424, 426: Cytotoxicity172
429–432A. terreus A8-4Mangrove-associated marine sediments, Guangxi, China/173
433A. insulicola 088708aZASediment, Hawaii/174
434A. sulphureus KMM 4640Sediment, Unknown placeCytotoxicity175
435–438A. versicolor MF030Sediment, Bohai Sea, China435: Antitubercular activity176
439–452A. ustus 094102Rhizosphere soil of the mangrove plant Bruguiera gymnorrhiza, Wenchang, Hainan, China444, 446, 451: Cytotoxicity177
453, 454A. effuses H1-1Mangrove rhizosphere soil, Fujian, China454: Cytotoxicity178–179
455–459A. westerdijkiae DFFSCS013Sediment (–2918 m), South China Sea457, 458: Cytotoxicity180
460–462A. sydowii MF357Sediment, Bohai Sea, China460, 462: Antimicrobial activity181
463–466A. aculeatusSediment, Langqi Island, Fujian, China464, 466: Cytotoxicity182
467–474A. versicolor HDN08-60Sediment, South China Sea474: Cytotoxicity;
Inhibition of PTKs		183
475–478A. oryzaeSediment, Langqi Island, Fujian, China475, 478: Cytotoxicity184
479–481A. oryzaeSediment, Langqi Island, Fujian, China/185
482A. ochraceusSediment, Sea of Japan/186
483–485A. glaucus HB1-19Mangrove rhizosphere soil, Fujian, China483, 484: DPPH-radical scavenging187
486A. glaucus HB1-19Mangrove rhizosphere soil, Fujian, ChinaCytotoxicity188
487–500A. sclerotiorum PT06-1Putian Sea Salt Field, Fujian, China487–490, 494, 497: Antimicrobial activity
488, 500: Cytotoxicity		189–191
501–503A. terreus PT06-2Putian Sea Salt Field, Fujian, China501, 502: Antimicrobial activity192
504, 505A. fumigates BM939Sediment (–760 m), Oi River, JapanCytotoxicity193
506Asperillus sp. MF-34Sea water, Mei-Zhou Gulf, Fujian, China/194
507, 508A. niger MF-16Sea water, Quanzhou Gulf, Fujian, China/195
509, 510Aspergillus sp. MF-93Sea water, Quanzhou Gulf, Fujian, ChinaAntivirus196
511A. versicolor ZBY-3Sea water (–800 m), Southeast PacificAntimicrobial activity; Cytotoxicity197
512–515A. versicolor CXCTD-06-6aSea water (–800 m), Pacific Ocean515: DPPH-radical scavenging198–199
516Aspergillus sp. CNM-713Unknown source/200
517A. nigerUnknown source/201


表选项




致谢
本课题组的王聪博士和马颖娜硕士在本文的写作及文献查阅过程中付出了大量艰辛的劳动，在此对其贡献表示感谢。

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