摘要
特殊的生态环境孕育了特殊的生物多样性，而特殊的生物多样性往往孕育着特殊的化学多样性和生物活性的多样性。为了寻找骨架新颖且具有良好治疗作用的新药先导化合物，本论文以不同生源环境分离得到的海洋和陆生真菌作为研究对象，开展活性次级代谢产物的结构和生物活性研究。研究主要内容包括：活性菌株的分离筛选；代谢产物的分离纯化及化学结构的鉴定和构型的确定；新化合物生合成途径的探索；单体化合物生物活性的初步评价；活性化合物作用靶点和活性机制的初步探讨。
从采集自不同纬度(山东、福建、广东、海南)的24个潮间带海泥、红树林根泥和火山口沉积物样品中共分离丝状真菌390株，采用海虾生物致死法和tsFt210细胞镜检细胞毒活性筛选模型，结合TLC及HPLC化学筛选，得到20株活性菌，从中选取火山口沉积物来源的桔青霉Penicillium citrinum HGY1-5和红树林根部海泥来源的灰绿曲霉Aspergillus glaucus HB1-19，以及其他来源的三株真菌—深海海泥来源的青霉Penicillium sp．F23-2和青霉Penicillium sp．F1，潮间带海泥来源的木霉Trichoderma sp．f-13—作为本论文的研究对象。
对5株目标活性菌株发酵产物运用萃取，薄层色谱，正相、反相硅胶柱色谱，LH-20凝胶柱色谱，反相高压液相等化学分离纯化手段，从桔青霉P．citrinumHGY1-5的代谢产物中分离得到47个单体化合物(1-47)；从灰绿曲霉A．glaucusHB1-19的代谢产物中分离得到了34个单体化合物(42，43，48-79)；从青霉Penicillium sp．F23-2的代谢产物中分离得到11个单体化合物(80-90)；从青霉Penicillium sp．F1的代谢产物中分离得到了10个单体化合物(91-100)；从木霉Trichoderma sp．f-13的代谢产物中分离得到了11个单体化合物(46，101-110)；另外，以桔青霉P．citrinum HGY1-5对甾体进行生物转化得到三个单体化合物(111-113)；对桔霉素二聚体17的化学转化得到一个人工产物(114)，共114个化合物。
继而，利用理化性质和波谱学方法(IR，UV，MS，NMR，CD，X-ray)结合化学反应的方法(Mosher法，对溴苯甲酰酯化等)阐明了全部1 14个化合物的化学结构(Fig．1)，结构类型按生合成来源分类包括：甾体类化合物21个(1-16，40，41，111-113)，萜类化合物6个(85-90)，聚酮类化合物56个(17-39，42-45，48-75，114)，生物碱类化合物19个(76-84，91-100)，sorbicillin衍生物11个(46，101-110)，脑苷酯类化合物1个(47)。其中发现新化合物63个，包括13个具有罕见的bicyclo[4．4．1]A／B环的C25甾体化合物(1，3-13，16)，2个新骨架的桔霉素三聚体(19，20)，13个结构新颖的桔霉素二聚体(17，18，21-24，26-28，32-34，114)，2个含有新颖的naphtho[1，2，3-de]chromene-2，7-dione骨架的灰绿霉素类聚酮化合物(48，49)，2个含有新颖的spiro[5．5]undecane螺环骨架的灰绿霉素类聚酮化合物(50，51)，14个蒽型的或萘型的芳香聚酮化合物(52-54，56，57，59-61，63-68)，2个meleagrin型生物碱(80，81，其中80是一个新颖的meleagrin型生物碱与conidiogenone型二萜链接形成的复合化合物)，2个roquefortine型二酮哌嗪生物碱(83，84)，6个罕见的conidiogenone型二萜(85-90，目前仅两例报道)，5个brevicompanine型二酮哌嗪生物碱(91-93，96，97)，2个sorbicillin衍生物(101，107)。在研究中，我们首次采用稳定同位素标记，化学结构转化和甾体微生物转化的方法确定了C25甾体(1-16)骨架的生合成来源和各侧链类型化合物的亲缘关系；我们对桔霉素(36)人工聚合和降解反应机制进行了探索研究；采用X-ray单晶衍射方法确定了新骨架化合物灰绿霉素A(48)的结构，采用同位素标记结合NMR的方法确定了螺环新骨架化合物灰绿霉素C(50)的结构，并进一步采用在线手性HPLC-CD和计算机量子化学CD模拟相结合的方法，确定了灰绿霉素C外消旋混合物的本质及两个对映异构体的绝对构型；采用NOESY和CD相结合的方法首次确定了conidiogenone型二萜(85-90)的绝对构型；采用NOESY和氨基酸手性HPLC分析相结合的方法确定了brevicompanine型二酮哌嗪生物碱(91-93，96，97)的绝对构型。
为了寻找化合物的治疗作用，我们采用抗肿瘤和神经保护两种不同的策略对单体化合物的生物活性进行评价。首先，采用MTT法、SRB法以及流式细胞术结合形态学检测的方法，对分离获得的单体化合物的抗肿瘤活性进行了初步评价，从中筛选出了20个活性化合物(细胞毒IC_(50)＜10μM)(17-22，24，46，48，49，61，80-82，86-88，90，102，114)，进一步采用ELESA和Western blot等方法对活性化合物的分子靶点和作用机制进行初步探索。其中：1．新骨架化合物灰绿霉素A(48)对A-549和HL-60细胞的IC_(50)分别为0．13和0．28μM；该化合物在10μM时对蛋白激酶具有抑制作用，抑制率分别为Src(40．5％)，KDR(43．4％)；在该浓度下灰绿霉素A(48)还可以明显的抑制拓扑异构酶Ⅱ的活性；初步的实验表明灰绿霉素A(48)对小鼠S_(180)肉瘤模型具有体内抗肿瘤活性；目前对灰绿霉素A(48)的临床前药效学评价正在深入进行当中。2．桔霉素聚合物17-20和114在1-10μM浓度下可以明显的诱导HL-60细胞发生凋亡，其作用具有时间依赖性和浓度依赖性；它们在10μM浓度下可以效应性的激活凋亡相关蛋白Caspase 3和8以及PARP，是一类新颖的肿瘤细胞凋亡诱导剂。3．Meleagrin生物碱82在10μM浓度下可以将HL-60细胞周期阻滞在G_2／M期，推测其作用机制可能与其9-OCH_3类似物oxaline一样，通过抑制微管蛋白聚合发挥作用；而生物碱与二萜链接型新骨架化合物meleagrin B(80)在10μM和5μM浓度下可以明显的诱导HL-60细胞发生凋亡，推测二萜片断的引入可能使其作用靶点发生了改变。4．Sorbicillin衍生物(46，101-110)对HL-60细胞的细胞毒测试表明，山梨酰基侧链2，3-双键还原会使相应的化合物细胞毒活性下降2-10倍，说明此类化合物侧链共轭系统与其抗肿瘤活性密切相关。
对于100μM浓度下没有表现出明显的细胞毒活性的化合物，采用LPS诱导的BV2小胶质细胞炎症拮抗模型或G-蛋白偶联受体12(GPR12)激活模型评测其潜在的神经保护活性，首次发现10个新活性化合物(1，2，8，9，12，91，92，94，96，97)。其中：1．Brevicompanine型二酮哌嗪生物碱92和97在0．1μg／ml～80μg／ml浓度范围内对LPS诱导的BV2小胶质细胞炎症模型具有明显的抑制活性，这是首次发现此类二酮哌嗪生物碱的抗炎活性。2．C25甾体化合物1，2，8，9和12在10μM浓度下可以明显的激活GPR12，促进cAMP的释放。这是首次发现C25甾体化合物潜在的治疗活性。
本论文从5株真菌次级代谢产物中共分离鉴定了63个新化合物，发现了五种新颖的化合物骨架类型，确定了其绝对构型，并对C25甾体，桔霉素衍生物和灰绿霉素类聚酮等新骨架化合物的生合成进行了系统的研究，丰富了天然产物的化学结构类型和生合成内容。经活性评价，共筛选出30个活性化合物(包括24个新化合物)，其中发现了一个新骨架的抗肿瘤先导化合物灰绿霉素A(48)，该化合物具有新颖的naphtho[1，2，3-de]chromene-2，7-dione骨架，体外细胞和分子水平有效，体内初步评价有效，是一个新颖的多靶点作用的抗肿瘤先导化合物；发现了两类新骨架的肿瘤凋亡诱导剂桔霉素聚合物17-20和生物碱与二萜链接型化合物meleagrin B(80)，为新药研究提供了重要的先导结构。共分离筛选获得20株抗肿瘤活性菌株，发现了三株能产生系列新骨架抗肿瘤活性化合物的真菌灰绿曲霉A．glaucus HB 1-1 9，桔青霉P．citrinum HGY1-5和青霉Penicillium sp．F23-2，为开发真菌抗肿瘤药物提供了重要的药用资源活性菌株。
Special environment may create specific biodiversity which can be endowed withunique chemical diversity and distinct bioactivities.In order to look for new leadcompounds with novel skeletons and potent bioactivities,a study was carried out toinvestigate the bioactive compounds derived from marine and terrestrial fungi.Studies include isolation and screening of bioactive fungal strains,purification andstructural elucidation of the secondary metabolites,exploring the biosyntheticpathways of the novel compounds,preliminary evaluation for bioactivities of purecompounds and the potential mechanisms and targets of the active compounds.
390 fungal strains were isolated from 24 samples,including near shore sediment,sediment around the mangrove roots,and volcano ash,collected at distinct latitudes(Shandong,Fujian,Guandong,and Hainan).Using brine shrimp lethality assay andtsFT210 cell line as bioactive screen model,together with applying the TLC andHPLC chemical screen assays,20 fungal strains were detected the cytotoxic activity.Among the bioactive strains,a volcano-ash derived fungus Penicillium citrinumHGY1-5 and a mangrove root sediment derived fungus Aspergillus glaucus HB1-19were picked out as the aimed strains.Two deep ocean sediment derived fungiPenicillium sp.F23-2 and Penicillium sp.F1,and an inshore sediment derived fungusTrichoderma sp.f-13 from other sources were also chosen.
In all,114 compounds were isolated and purified,from the bioactive extracts of the5 aimed strains,by using solvent extraction,silica gel column,Sephadex LH20,PHPLC and etc.From fungus P.citrinum HGY1-5,47 compounds (1-47) wereisolated;from A.glaucus HB1-19,34 compounds (42,43,48-79) were isolated;fromPenicillium sp.F23-2,11 compounds (80-90) were isolated;from Penicillium sp.F1,10 compounds (91-100) were isolated;from Trichoderma sp.f-13,11 compounds (46,101-110) were isolated.Additionally,3 compounds (111-113) were obtained bybiotransformation of steroids using P.citrinum HGY1-5 and another compound (114)was prepared by chemical transformation of the citrinin dimmer 17.
By means ofphysico-chemical properties and spectral analysis (IR,UV,MS,NMR,X-ray,etc.),structures of all the 114 pure compounds were respectively determined.Among them there are 21 steroids (1-16,40,41,111-113),6 diterpenes (85-90),56polyketides (17-39,42-45,48-75,114),19 alkaloids (76-84,91-100),11 sorbicillinderivatives (46,101-110),and one cerebroside (47).63 compounds are new,including13 C25 steroids (1,3-13,16) with rare bicyclo[4.4.1] A/B rings,2 citrinin trimers (19,20) with novel skeletons,13 novel citrinin dimmers (17,18,21-24,26-28,32-34,114),2 aspergiolide polyketides (48,49) with novel naphtho[1,2,3-de]chromene-2,7-dioneskeltons,2 aspergiolide polyketides (50,51) with novel spiro[5.5]undecane skeletons,14 anthracene or naphthalene polyketides (52-54,56,57,59-61,63-68),2 meleagrinalkaloids(80,81,80 is a novel complex compound with a meleagrin alkaloid moietyand a conidiogenone diterpene moiety),2 roquefortine diketopiperazine alkaloids (83,84),6 conidiogenone diterpenes (85-90),5 brevicompanine diketopiperazine alkaloids(91-93,96,97),and 2 sorbicillin derivatives (101,107).In the study,we firstinvestegated the biosynthetic origin of the C25 steroids and the chemical relationshipsof the distict side chains by the combination of the stable isotope labeling experiments,chemical transformation,and microbial transformation of several steroids;weexplored the polymerization and degradation mechanism of citrinin (36).We firstdetermined the structure of the novle compound aspergiolide A (48) using X-raycrystallographic analysis.We first elucidated the constitution of a novel spirocyclicaromatic polyketide aspergiolide C (50) by a combination of spectroscopic methodsand isotope-labeling experiments.Aspergiolide C is a racemic mixture,its twoenantiomers were resolved by HPLC on a chiral phase and their absoluteconfigurations were assigned online,right from the peaks in the chromatogram,by acombination of HPLC-CD and quantum chemical CD calculations.We first established the absolute configurations of the conidiogenone diterpenes (85-90) by thecombination of NOESY and CD spectra.We established the absolute configurationsof the brevicompanine diketopiperazine alkaloids (91-93,96,97) by the combinationof the NOESY spectrum and chiral HPLC analysis for amino acids.
In order to look for the potential curing effects of the compounds isolated,twodifferent strategies,antitumor and neuro-protection were applied.The antitumoractivities against several cancer cell lines of these compounds were assayed by MTT,SRB and flow cytometry methods.Among them 20 compounds (17-22,24,46,48,49,61,80-82,86-88,90,102,114) with significant bioactivities (cytotoxic,IC_(50)＜10μM)were found.The molecular targets or mechanisms of the active compounds werefurther explored using the methods such as ELESA and Western blot.1.The novelcompound aspergiolide A (48) showed potent cytotoxic activities against the A-549and HL-60 cell lines with the IC_(50) values at 0.13 and 0.28μM.At 10μM,aspergiolideA (48) inhibited the protein kinases Src and KDR with the inhibitory rates at 40.5%and 43.4%,respectively.At the same concentration,it could also inhibitedtoposiomerose II potently.Aspergiolide A (48) also showed in vivo antitumor activitieson the S_(180)-sarcoma mice model.2.Citrinin trimers and dimers 17-20 and 114 couldinduce HL-60 cell apoptosis at 1-10μM.The activities were confirmed by the effectsof these compounds to activate caspases 3 and 8 and also PARP at 10μM.3.Meleagrin alkaloid 82 could block HL-60 cells through G_2/M phase at 10μM.Itindicted that this compound may inhibit tubulin polymerization as its 9-OCH_3 analogoxaline.The novel complex compound meleagrin B (80) could induce HL-60 cellapoptosis at 5 and 10μM.It indicated that the introduction of the diterpene moietyinto the structure may alter the the target of the alkaloid.4.The cytotoxic assay ofsorbicillin dericatives (46,101-110) showed both monomers and dimers withfull-unsaturated side chains all showed higher cytotoxity than the correspondingdihydro analogs.
The potential neuro-protection activities of those without obvious cytotoxicactivities at 100μM were evaluated using the lipopolysaccharide (LPS)-inducedinflammation inhibition assay in BV2 microglial cell line or the cAMP generationassay in GPR12-CHO and WT-CHO cells.Ten compounds (1,2,8,9,12,91,92,94,96,97) were active,including:1.Brevicompanine diketopiperazine alkaloids 92 and97 showed potential anti-inflammatory effects on LPS-induced inflammatory model in BV2 microglial cells and Raw264.7 macrophages at 0.1μg/ml～80μg/ml.This isthe first report of the anti-inflammatory effect of such diketopiperazine alkaloids.2.C25 steroids 1,2,8,9 and 12 could induce the production of cAMP by activatingGPR12.This is the first report of the therapeutical effect of the C25 steroids.
In this study,63 new compounds were isolated and identified from 5 aimed fungalstrains.Five novel skeleton types were discovered.We established their absoluteconfigurations and systematically studied the biosynthesis of some novle skeletoncompounds including C25 steroids,citrinin derivatives and aspergiolide polyketides.It enriched the chemical structure types and biosynthetic contents of natural products.Furthermore,30 active compounds were discovered (including 24 new compounds)including an antitumor lead compound aspergiolide A (48) with novelnaphtho[1,2,3-de]chromene-2,7-dione skeleton.This compound is active both in vitroand in vivo.It is a novel molecular-targeted antitumor lead compound which hasentered pre clinical study phase.We also discovered novel apopotosis inducers citrninderivatives 17-20 and meleagrin B (80).It provided important lead structures for drugdiscovery.Twenty antitumor strains were screened from 390 fungal strains isolatedfrom 24 marine or terrestrial samples.Three important fungal strains,Aspergillusglaucus HB 1-19,Penicillium citrinum HGY1-5,and Penicillium sp.F23-2,which canproduce novel antitumor compounds,were discovered.It provided importantbioactive fungal strains for drug discovery.
引文
1.Chin,Y.W.;Balunas,M.J.;Chai,H.B;Kinghorn,A.D.Drug discovery from natural sources.The AAPSJournal,2006,8,E239-E253.
2．朱天骄，崔承彬，顾谦群等．海洋微生物的分离培养及抗肿瘤活性初筛．青岛海洋大学学报，2002，32，123-126．
3．于垂亮，崔承彬，朱天骄，顾谦群，刘红兵，方玉春，韩冰，蔡兵．海洋真菌的分离、抗肿瘤活性筛选与发酵条件研究．中国海洋药物杂志，2004，23，1-6．
4．韩小贤，崔承彬，刘红兵，朱天骄，顾谦群，李冬，温江妮．海洋微生物抗肿瘤活性菌株的分级组合筛选．中国海洋大学学报，2005，25，38-42
5.Solis P.N.,Wright C.W.,Anderson M.M.,Gupta M.P.,Phillipson J.D.A microwell cytotoxicity assay using Artemia salina (brine shrimp).Planta.Med.,1993,59,250-252.
6.Meyer B.N.,Ferrigni N.R.,Putnam J.E.,Jacobsen L.B.,Nichols D.E.,McLaughlin J.L.Brine Shrimp:A convenient general bioassay for active plant constituents.Planta.Med.,1982,45,31-34.
7．张永杰，王建锋，黄耀坚等．4种裸子植物内生真菌抗肿瘤菌株的筛选．厦门大学学报，2002，41，804-809．
8．杰利·L·麦克劳林，顾哲明．两种简易的抗肿瘤活性初筛方法．中国中药杂志，1997，23，617-619．
1.Kozlovsky,A.G.;Zhelifonova,V.P.;Ozerskaya,S.M.;Vinokurova,N.G.;Adanin,V.M.;Grafe,U.Cyclocitrinol,a new fungal metabolite from Penicillium citrinum.Pharmazie 2000,55,470-471.
2.Amagata,T.;Amagata,A.;Tenney,K.;Valeriote,F.A.;Lobkovsky,E.;Clardy,J.;Crews,P.Unusual C25 Steroids Produced by a Sponge-Derived Penicillium citrinum.Org.Lett.2003,5,4393-4396.
3.Andrey,M.R.M.;Edson,R.F.;Ant(?)nio,G.F.;Lourivaldo,S.S.C25 Steroid Epimers Produced by Penicillium janthinellum,a Fungus Isolated from Fruits Melia azedarach.J.Braz.Chem.Soc.2005,16,1342-1346.
4.Bruce,B.J.;Shengjun,W.;Herman,L.A.Trichoverroid Stereoisomers.J.Nat.Prod.1996,59,254-261.
5.Nelson,M.E.Nonactin biosynthesis:Stable isotope precursors studies.PhD dissertation of the ohio state university 2001.
6.Yang,X.Studies on the biosynthesis of oudenone and verucopeptin.PhD dissertation of the Coneordia university 2000.
7.Volkman,J.K.Sterols in microorganisms.Appl.Microbiol.Biotechnol.2003,60,495-506.
8.Masao,H.;Asami,K.;Yoshihisa,A.;Takafumi,Y.Blazeispirol A,an unprecedented skeleton from the cultured nycelia of the fungus Agaricus blazei.Tetrahedron Lett.2000,41,6101-6104.
9.Omura,S.;Tsuzuki,K.;Tanaka,Y.Valine as a precursor of butyrate unit in the biosynthesis of macrolide aglycone.J.Antibiot.1983,36,616-619.
10.Pospisil,S.;Sedmera,P.;Havranek,M.;Krumphanzi,J.;Vanek,Z.Biosyntheis of monensins A and B.J.Antibiot.1983,36,617-619.
11.Swanson,K.M.;Hohl,R.J.Anti-cancer therapy:targeting the mevalonate pathway.Curr Cancer Drug Targets 2006,6,15-37.
12.Fernandes,P.;Cruz,A.;Angelova,B.;Pinheiro,H.M.;Cabral,J.M.S.Microbial conversion of steroid compounds:recent developments.Enzyme and Microbial Technology 2003,32,688-705.
13.Mihovilovic,M.D.;Müller,B.;Stanetty,P.Monooxygenase-mediated Baeyer-Villiger oxidations.Eur.J.Org.Chem.2002,3711-3730.
14.Brandt,M.;Levy,M.A.3β-Hydroxy-Δ~5-steroid dehydrogenase/3-keto-Δ~5-steroid isomerase from bovine mechanism of the dehydrogenase adrenals:mechanism of inhibition by 3-oxo-4-aza steroids and kinetic mechanism of the dehydrogense.Biochemistry 1989,28,140-148.
15.Decr(?)au,R.A.;Marson,C.M.;Simith,K.E.;Behan,J.M.Production of malodorous steroids from androsta-5,16-dienes and androsta-4,16-dienes by Corynebacteria and other human axillary bacteria.J.Steroid.Biochem.Mol.Biol.2003,87,327-336.
16.Bates,M.L.;Reid,W.W.Duality of pathways in the oxidation of ergosteol to its peroxide in vivo.J.C.S.Chem.Comm.1976,44-45.
17.Uhlenbrock,K.;Gassenhuber,H.;Kostenis,E.Sphingosine 1-phosphate is a ligand of the human gpr3,gpr6 and gprl2 family of constitutively active G protein-coupled receptors.Cellular Signalling 2002,14,941-953.
18.Hinckley,M.;Vaccari,S.;Horner,K.;Chen,R.;Conti,M.The G-protein-coupled receptors GPR3 and GPR12 are involved in cAMPsignaling and maintenance of meiotic arrest in rodent oocytes.Developmental Biology 2005,287,249-261.
19.Tanaka,S.;Ishii,K.;Kasai,K.;Yoon,S.O.;Saeki,Y.Neural Expression of G Protein-coupled Receptors GPR3,GPR6,and GPR12 Up-regulates Cyclic AMP Levels and Promotes Neurite Outgrowth.J.Biol.Chem.2007,282,10506-10515.
20.Hetherington,A.C.;Raistrick,H.Philos.Trans.R.Soc.London,Ser.B 1931,220,269-296.
21.Brown,J.P.;Cartwright,N.J.;Robertson,A.;Whalley,W.B.Structure of citrinin.Nature 1948,162,72-73.
22.Hill,R.K.;Gardella,L.A.The absolute configuration of citrinin.J.Org.Chem.1964,29,766-767.
23.Kovac,S.;Nemec,P.;Betina,V.;Balan,J.Chemical structure of citrinin.Nature 1961,190,1104-1105.
24.Colombo,L.;Gennari,C.;Potenza,D.;Scolastico,C.;Aragozzini,F.;Merendi,C.Biosynthesis of Citrinin and Synthesis of its Biogenetic Precursors.J.Chem.Soc.,Perkin Trans.1 1981,2594-2597.
25. Barber, J.; Chapman, A. C; Howard, T. D. The use of sodium [2-~2H_3,1,2-~(13)C_2] acetate in determining the biosynthetic origins of hydrogen atoms in fungal metabolites: the biosynthesis of citrinin by Penicillium citrinum. J. Antibiot. 1987, 40, 245-248.
26. Krogh, P.. Hasselager, E.; Friis, P. Isolation of two nephrotoxic compounds from Penicillium viridicatum Westling: Citrinin and oxalic acid. Ada Pathol. Microbiol. Scand., Sect. B: Microbiol. Immunol. 1970, 78, 401-413.
27. Betina,V. Mycotoxins: Chemical, Biological, and Environmental Aspects, Elsevier, Amsterdam, 1989.
28. Kitabatake, N.; Trivedi, A. B.; Doi, E. Thermal Decomposition and Detoxification of Citrinin under Various Moisture Conditions. J. Agric. Food Chem., 1991, 39,2240-2244.
29. Hirota, M.; Menta, A. B.; Yoneyama K.; Kitabatake, N. A major decomposition product, citrinin H2, from citrinin on heating with moisture. Biosci., Biotechnol., Biochem. 2002, 66, 206-210.
30. Trivedi, A. B.; Hirota, M.; Etsushiro, D.; Kitabatake, N. Formation of a new toxic compound, citrinin HI, from citrinin on mild heating in water. J. Chem. Soc, Perkin Trans. 1, 1993, 2167-2171.
31. Clark, B. R.; Capon, R. J.; Lacey, E.; Tennant, S.; Gill, J. H. Citrinin revisited: from monomers to dimers and beyond. Org. Biomol. Chem. 2006, 4, 1520-1528.
32. Wakana, D.; Hosoe, T.; Itabashi, T.; Okada, K.;Takaki, G. M. C.; Yahuchi, T.; Fukushima, K.; Kawai, K. New citrinin derivatives isolated from Penicillium citrinum. J. Nat. Med., 2006, 60, 279-284.
33. Lu, Z.; Lin, Z.; Wang, W.; Du, L.; Zhu, T.; Fang, Y; Gu, Q.; Zhu, W. Two New Citrinin Dimers of the Halotolerant Fungus Penicillium sp. B-57. J. Nat. Prod. 2008, 71, 543-546.
34. Kadam, S.; Poddig, J.; Humphpey, P.; Karwowski, J.; Jackson, M.; Tennent, S.; Fung, L.; Hochlowski, J.; Rasmussen, R.; Mcalpine, J. Citrinin hydrate and radicinin: human rhinovirus 3C-protease inhibitors discovered in a target-directed microbial screen. J. Antibiotic. 1994, 47, 836-839.
35. Barber, J.; Cornford, J. L.; Howard, T. D.; Sharpies, D. The structure of citrinin in vivo. J. Chem. Soc. Perkin. Trans. I1987, 2743-2744.
36. Poupko, R.; Luz, Z. Carbon-13 NMR of citrinin in the solid state and in solutions. J. Phys. Chem. A 1997,101, 5097-5102.
37. Chen, H. C; Chin, Y. S.; Chien, C. C; Ying, C. T. 2,3,4-Trimethyl-5,7-dihydroxy-2,3-dihydrobenzofuran, a novel antioxidant, from Penicillium citrinum F5. J. Nat. Prod. 2002, 65, 740-741.
38. Snatzke, G. Circulardichroismus-Ⅷ.Modifizierung der octantenregel f(?)r α,β-unges(?)ttigte ketone: theorie. Tetrahedron 1965, 21, 413-419.
39. Chien, M. M.; Schiff, P. L., Jr.; Slatkin, D. J.; Knapp, J. E. Metabolites of Aspergilli.Ⅲ. The isolation of citrinin, dihydrocitrinone and sclerin from Aspergillus carneus. Lloydia 1977,40,301-302.
40. Yu, F.; Liao, Y.; Chang, C; Liu, B. Citrinin induces apoptosis in HL-60 cells via activation of the mitochondrial pathway. Toxicology Letters 2006,767, 143-151.
41. Skehan, P.; Storeng, R.;Scudiero, D.; Monks, A.; Mc Mahon, J., Vistica, D. W.; Bokesch, H.; Kenney, S.; Boyd, M. R. New colorimetric cytotoxicity assay for anticancer drug screening. J. Natl. Cancer Inst. 1990, 82 , 1107-1112.
42. Mossman, T.Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assay. J.Immunol. Meth., 1983, 65, 55-63.
43. Takaishi, Y.; Uda, M.; Ohashi, T.; Nakano, K.; Murakami, K.; Tomimatsu, T. Glycosides of ergosterol derivatives from Hericum erinacens. Phytochemstry 1991, 30, 4117-4120.
44. A. A. Leslie, G.; Yalamanchili, G.; Francis, J. S.; Carl, D. Minor and trace sterols in marine invertebrates. 26. Isolation and structure elucidation of nine new 5a, 8a-epidioxy sterols from four marine organisms. J. Org. Chem. 1981, 46, 3860-3866.
45. Farmamarzi, M. A.; Yazdi, M. T.; Amini, M.; Mohseni, F. A.; Zarrini, G.; Amani, A.; Shafiee, A. Microbial poduction of testosterone and testololactone in the culune of Aspergillus terres. World J. Microb. Biot. 2004, 20, 657-660.
46. Aknin, M.; Viracaoundin, I.; Faure, R.; Gaydou, E. M. 5α,8α-Epidoxycholest-6-en-3-β-ol from three cone snails of the Indian ocean. JAOCS 1998, 75, 1679-1681.
47. Picciali, V.; Sica, D. Four new trihydroxylated steroids from the sponge Spongionella gracilis. J. Nat. Prod. 1987, 50, 915-920.
48. Iorizzi, M.; Minale, L.; Riccio, R. Polar steroids from the marine scallop Patinopecten yessoensis. J. Nat. Prod. 1988, 57, 1098-1103.
49. Kawgishi, H.; Katsumi, R.; Sazawa, T.; Mizuno, T.; Hagiwara, T.; Nakmura, T. Cytotoxic steroids from the Mushroom Agaricus blazei. Phytochemistry 1988, 27, 2777-2779.
50. Tokoroyama, T.; Kubota, T. The biosynthesis of sclerin. J. Chem. Soc. (C) 1971, 2703-2708.
51. Huneck, S. Pseudocyphellarins A and B, two fully substituted depsides from the lichen Pseudocvphellaria endochrysea. Phytochemistry 1984, 23, 431-434.
52. Jiang, T.; Li, J.; Fu, H.; Ji, Y.; Lin, W. New cerebroside analogues from marine fungus Aspergillus flavipes. Journal of Harbin University of Commerce Natural Sciences Edition 2002, 75, 597-602.
1.Julia,S.;Christian,H.Advances in cloning,functional analysis and heterologous expression of fungal polyketide synthase genes.J.Biotechnol.2006,124,690-703.
2.Heidrun,A.;Ilham,K.;Hans,Z.;Hartmut,L.Metabolic Products of Microorganisms.185.* The Anthraquinones of the Aspergillus glaucus Group.I.Occurrence,Isolation,Identification and Antimicrobial Activity.Arch.Microbiol.1980,126,223-230.
3.Bachmann,M.;Luthy,J.;Schlatter,C.Toxicity and Mutagenicity of Molds of the Aspergillus glaucus Group,Identification of Physcion and Three Related Anthraquinones as Main Toxic Constituents from Aspergillus che valieri.J.Agric.Food Chem.1979,27,1342-1347.
4.George,B.;Dieter,H.K.;Shank,R.C.;Steven,M.W.;Wogan,G.N.Structure and Synthesis of Kotanin and Desmethylkotanin,Metabolites ofAspergillus glaucus.J.Org.Chem.1971,36,1143-1147.
5.Bringmann,G.;Busemann,S.In Natural Product Analysis:Chromatography,Spectroscopy,Biological Testing;Schreier,P.,Herderich,M.,Humpf,H.-U.,Schwab,W.,Eds.;Vieweg:Wiesbaden,1998,p 195.
6.Tao,K.;Du,L.;Sun,X.;Cai,M.;Zhu,T.Zhou,X.;Gu,Q.;Zhang,Y.Biosynthesis of aspergiolide A,a novel antitumor compound by a marine-derived fungus Aspergillus glaucus via the polyketide pathway.Tetrahedron letters 2009,50,1082-1085.
7.Skehan,P.;Storeng,R.;Scudiero,D.;Monks,A.;Mc Mahon,J.,Vistica,D.W.;Bokesch,H.;Kenney,S.;Boyd,M.R.New colorimetric cytotoxicity assay for anticancer drug screening.J.Natl.Cancer Inst.1990,82,1107-1112.
8.Mossman,T.Rapid colorimetric assay for cellular growth and survival:application to proliferation and cytotoxicity assay.J.Immunol.Meth.,1983,65,55-63.
9.Lin,L.G.;Xie,H.;Li,H.L.;Tong,L.J.;Tang,C.P.;Ke,C.Q.;Liu,Q.F.;Lin,L.P.;Geng,M.Y.;Jiang,H.;Zhao,W.M.;Ding,J.;Ye,Y.Naturally Occurring Homoisoflavonoids Function as Potent Protein Tyrosine Kinase Inhibitors by c-Src-Based High-Throughput Screening.J.Med.Chem.2008,51,4419-4429.
10. Lin, C. N.; Lu, C. M; Lin, H. C; Ko, F. N.; Teng, C. M. Novel antiplatelet naphthalene from Rhamnus nakaharai. J. Nat. Prod. 1995, 55, 1934-1940.
11. Thomas, E. W.; Harry, P. C. H.; Terry, E. N.; Nick, A. M. The chemical synthesis and nuclear magnetic resonance spectroscopy of adenosylco balamin selectively enriched with carbon-13. Biochemistry 1974,13, 2650-2655.
12. Li, Y.; Li, X.; Lee, U.; Kang, J. S.; Choi, H. D.; Sona, B. W. A new radical scavenging anthracene glycoside, asperflavin ribofuranoside, and polyketides from a marine isolate of the fungus Microsporum. Chem. Pharm. Bull. 2006, 54, 882-883.
13. Robert, K. N.; Harry, W. D.; Hewitt, G. F. Jr. New benzoyl derivatives of D-ribofuranose and aldehyde-D-ribose. The preparation of crystalline 2,3,5-tri-O-benzoyI-β-D-ribose from D-Ribose. J. Am. Chem. Soc. 1954,16, 763-767.
14. Anthony, S. S.; Robert, B. [~(13)C]-Enriched tetroses and tetrofuranosides: an evaluation of the relationship between NMR parameters and furanosyl ring conformation. J. Org. Chem. 1984, 49, 3292-3300.
15. Fujimoto, H.; Fujimaki, T.; Okuyama, E.; Yamazaki, M. Immunomodulatory constituents from an ascomycete, Microasus tardifaciens. Chem. Pharm. Bull. 1999, 47, 1426-1432.
16. John, F. G. New metabolic products of Aspergillus f/avv.s. Part II. asperflavin, anhydroasperflavin, and 5,7-dihydroxy-4-methylphthalide. J. Chem. Soc. Perkin Trans. 1 1972,2406-2411.
17. Bringmann, G.; M(?)nchbach, M.; Messer, K.; Koppler, D.; Michel, M.; Schupp, O.; Wenzel, M.; Louis, A.M. Cis- and tnans-isoshinanolone from Dioncophyllum thollonii: absolute configuration of two 'known', wide-spread natural products. Phytochemistry 1999, 51, 693-699.
18. Bringmann, G.; Messer, K.; Saeb, W.; Peters, E. M.; Peters, K. The absolute configuration of (+)-isoshinanolone and in situ LC±CD analysis of its stereoisomers from crude extracts.Phytochemistry 2001, 56, 387-391.
19. Politi, M.; Sanogo, R.; Ndjoko, K.; Guilet, D.; Wolfender, J. L.; Hostettmann, K.; Morelli, I. HPLC-UV/PAD and HPLC-MS analyses of leaf and root extracts of vismia guineensis and isolation and identification of two new bianthrones. Phytochem. Anal. 2004, 75, 355-364.
20. Monache, G. D.; Rosa, M. C.;Scurria, R. Monacelli, B.; Pasqua, G.;Olio,G. D.; Botta, B. Metabolites from in vitro cultures of Cassia didymobotrya. Phytochemistry 1991, 30, 1849-1854.
21. Mai, L. P.; Gueritte, F.; Dumontet, V.; Tri, M. V.; Hill, B.; Thoison, O.; Guenard, D.; Sevenet, T. Cytotoxicity of rhamnosylanthraquinones and rhamnosylanthrones from Rhamnus nepalensis. J. Nat. Prod. 2001, 64, 1162-1168.
22. Donald, W. C; John, S. E.; Warwick, D. R. Oxidation of emodin anthrone and stereochemistry of emodin bianthrone. Aust. J. Chem. 1976, 29, 1535-1548.
23. Danielsen, K.; Aksnes, D. W. NMR Study of some anthraquinones from Rhubarb. Magn. Reson. Chem. 1992, 30, 359-360.
24. Heidrun, A.; Ilham, K.; Hans, Z.; Hartmut, L. Metabolic Products of Microorganisms. 185. The Anthraquinones of the Aspergillus glaucus Group. I. Occurrence, Isolation, Identification and Antimicrobial Activity. Arch. Microbiol. 1980,126, 223-230.
25. Wang, W.; Zhu, T.; Tao, H.; Lu, Z.; Fang, Y.; Gu, Q.; Zhu, W. Two new cytotoxic quinone type compounds from the halotolerant fungus Aspergillus variecolor. J. Antibiot. 2007, 60, 603-607.
26. Engstrom, K.; Brishammar, S.; Svensson, C; Bengtsson, M.; Anderson, R. Anthraquinones from some Drechslera species and Bipolaris sorokiniana. Mycol. Res. 1993, 97, 381-384.
27. Fujimoto, H.; Nakamura, E.; Okuyama, E.; Ishibashi, M. Six Immunosuppressive Features from an Ascomycete, Zopfiella longicaudata, Found in a Screening Study Monitored by Immunomodulatory Activity. Chem. Pharm. Bull. 2004, 52, 1005-1008.
28. Mehandale, A. R.; Rama Rao, A. V.; Shaikh, I. N.; Venkataraman, K.Desoxyerythrolaccin and laccaic acid D. Tetrahedron left. 1968,18, 2231-2234.
29. Arai, K.; Aoki, Y.; Yamamoto, Y. Asperinines A and B, dimeric tetrahydro- anthracene derivatives from Aspergillus ruber. Chem. Pharm. Bull, 1989, 37, 621-625.
30. Wang, W; Zhu, T.; Tao, H.; Lu, Z.; Fang, Y; Gu, Q.; Zhu, W. Variecolortide A-C, three Novel Oxa-spiro-cyclodipeptides from the Halotolerant Fungus strain Aspergillus variecolor B-17. Chemistry & Biodiversity 2007, 4, 2913-2919.
31. Kuo Y. H.; Lee, P. H.; Wein, Y. S. Four New Compounds from the Seeds of Cassia fistula. J. Nat. Prod. 2002, 65, 1165-1167.
32. Shen, B. Biosynthesis of Aromatic Polyketides. Top. Curr. Chem. 2000,209, 1-51.
33. Nagasawa, H.; Isogai, A.; Suzuki, A. et al. Carbon-13 NMR spectra and stereochemistry of isoechinulins A, B and C.Agr. Biol. Chem. 1979, 43, 1759-1763.
34. Takashi, H.; Kouzou, N.; Yuichi, H. A new metabolite, L-alanyl-L-tryptophan anhydride from Aspergillus chevalieri. Agr. Boil. Chem. 1976, 40, 2487.
35. Fujimoto, H.; Fujimaki, T.; Okuyama, E. et al. Immunomodulatory constituents from an ascomycete, Microascus tardifaciens. Chem. Pharm. Bull. 1999, 47, 1426-1432.
36. Marchelli, R.; Dossena, A.; Pochini, A.; Dradi, E. The structures of five new didehydropeptides related to neoechinulin, isolated from Aspergillus amstelodami. J. Chem. Soc. Perkin I 1977, 713-717.
1.Scott,P.M.;Merrien,M.A.;Polonsky,J.Roquefortine and Isofumigaclavine A,Metabolites from Penicillium roqueforti.Experientia 1976,32,140-142.
2.Ohmomo,S.;Oguma,K.;Ohashi,T.;Abe,M.Isolation of a new indole alkaloid,roquefortine D,from the cultures of Penicillium roqueforti.Agric.Biol.Chem.1978,42,2387-2389.
3.Musuku,A.;Selala,M.I.;de Bruyne,T.;Claeys,M.;Schepens,P.J.C.;Tsatsakis,A.;Shtilman,M.I.Isolation and structure determination of a new roquefortine-related mycotoxin from Penicillium verrucosum var.Cyclopium isolated from cassava.J.Nat.Prod.1994,57,983-987.
4.Kozlovsky,A.G.;Vinokurova,N.G.;Solov'eva,T.F.;Buzilova,I.G.Microfungal nitrogen-containing secondary metabolites.Appl.Biochem.Microbiol.1996,32,39-48.
5.Kozlovsky,A.G.;Zhelifonova,V.P.;Antipova,T.V.;Adanin,V.M.;Ozerskaya,S.M.;Ivanushkina,N.E.;Gollmick,F.A.;Graefe,U.A new 16N-carboxyethyl derivative of 3,12-dihydroroquefortin.Heterocycles 2003,60,1639-1644.
6.Steyn,P.S.;Vleggaa,R.Roquefortine,an Intermediate in the Biosynthesis of Oxaline in Cultures of Penicillium oxalicum.J.Chem.Soc.Chem.Comm.1983,560-561.
7.Clark,B.;Capon,R.J.;Lacey,E.;Tennant,S.;Gill,J.H.Roquefortine E,a Diketopiperazine from an Australian Isolate of Gymnoascus reessii.J.Nat.Prod.2005,68,1661-1664.
8.Kawai,K.;Nozawa,K.;Nakajima,S.;Iitaka,Y.Studies on fungal products.Ⅶ.The structures ofmeleagrin and 9-O-p-bromobenzoylmeleagrin.Chem.Pharm.Bull 1984,32,94-98.
9.Steyn,P.S.The isolation,structure and absolute configuration ofsecalonic acid D,the toxic metabolite of Penicillium oxalium.Tetrahedron,1970,26,51-57.
10.Nagel,D.W.;Pachler,K.G.R.;Steyn,P.S.;Wessels,P.L.;Gafner,G.;Kruger,G.J.X-Ray Structure of Oxaline:a Novel Alkaloid from Penicillium oxalicurn.J.Chem.Soc.Chem.Comm.1974,1021-1022.
11. Koizumi, Y.; Arai, M.; Tomoda, H.; Omura, S. Oxaline, a fungal alkaloid, arrests the cell cycle in M phase by inhibition of tubulin polymerization. Biochimica et Biophysica Acta 2004,1693, 47-55.
12. Kopp, B.; Rehm, H. J. European J. Antimicrobial Action of Roquefortine. Appl. Microbiol.Biotechnol. 1979, 6, 397-401.
13. Aninat, C; Hayashi, Y.; Andre, F.; Delaforge, M. Molecular Requirements for Inhibition of Cytochrome P450 Activities by Roquefortine. Chem. Res. Toxicol. 2001,14, 1259-1265.
14. Kusch, J.; Rehm, H. J. Regulation aspects of roquefortine production by free and Ca-alginate immobilized mycelia of Penicillium roqueforti. Appl. Microbiol. Biotechnol. 1986, 23,394-399.
15. Reshetilova, T. A.; Vinokurova, N. G; Khmelenina, V. N.; Kozlovskii, A. G. The role of roquefortine in the synthesis of alkaloids meleagrine, glandicolines A and B, and oxaline in fungi Penicillium glandicola and P. atramentosum. Microbiology 1995, 64, 27-29.
16. Williams, R. M.; Stoching, E. M; Sanz-Cervera, J. F. Biosynthesis of Prenylated Alkaloids Derived from Tryptophan. Topics in Current Chemistry 2000, 209, 97-173.
17. Roncal, T.; Cordobes, S.; Ugalde, U.; He, Y.; Sterner.O. Novel diterpenes with potent conidiation inducing activity. Tetrahedron Lett. 2002, 43, 6799-6802.
18. Yamaguchi, T.; Nozawa, K.; Nakajima, S.; Kawai, K.; Udagawa, S. Absolute configuration of roquefortine C, a tremorgenic mycotoxin. Maikotokishin 1991, 34, 29-32.
19. Vleggaar, R.; Wessels, P. L. Stereochemistry of the Dehydrogenation of (2s)-Histidine in the Biosynthesis of Roquefortine and Oxaline. J. Chem. Soc. Chem. Comm. 1980, 160-162.
20. Skehan, P.; Storeng, R.;Scudiero, D.;Monks, A.; Mc Mahon, J., Vistica, D. W.; Bokesch, H.;Kenney, S.; Boyd, M. R. New colorimetric cytotoxicity assay for anticancer drug screening. J. Nad. Cancer Inst. 1990, 82 , 1107-1112.
21. Mossman, T.Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assay. J.Immunol. Meth., 1983, 65, 55-63.
1.Kusano,M.;Sotoma,G.;Koshino,H.;Uzawa,J.;Chijimatsu,M.;Fujioka,S.;Kawano,T.;Kimura,Y.Brevicompanines A and B:new plant growth regulators produced by the fungus,Penicillium brevicompactum.J.Chem.Soc.,Perkin Trans.1 1998,2823-2826.
2.Kimura,Y.;Sawada,A.;Kuramata,M.;Kusano,M.;Fujioka,S.;Kawano,T.;Shimada A.Brevicompanine C,Cyclo-(D-Ile-L-Trp),and Cyclo-(D-Leu-L-Trp),Plant Growth Regulators from Penicillium brevi-compactum.J.Nat.Prod.2005,68,237-239.
3.Sprog(?)e,K.;Manniche,S.;Larsenb,T.O.;Christophersen,C.Janoxepin and brevicompanine B:antiplasmodial metabolites from the fungus Aspergillusjanus.Tetrahedron,2005,61,8718-8721.
4.Matsumura,K.;Kitahara,T.Synthesis ofbrevicompanines,plant growth regulators.Heterocycles 2000,55,727-733.
5.Arai,K.;Kimura,K.;Mushiroda,T.;Yamamoto,Y.Structures of fructigenines A and B,new alkaloids isolated from Penicillium fructigenum TAKEUCHI.Chem.Pham.Bull.1989,37,2937-2939.
6.Wang,W.L.;Lu,Z.Y.;Tao,H.W.;Zhu,T.J.;Fang,Y.C.;Gu,Q.Q.;Zhu,W.M.Isoechinulin-type Alkaloids,Variecolorins A-L,from Halotolerant Aspergillus Wariecolor.J.Nat.Prod.2007,70,1558-1564.
7.Shiono,Y.;Akiyama,K.;Hayashi,H.New okaramine congeners,okamines J,K,L,M and related compounds,from Penicillium simplicissimum ATCC 90288.Biosei.Biotechnol.Biochem.1999,63,1910-1920.
8.Heguy,A.;Cai,P.;Meyn,P.;Houck,D.;Russo,S.;Michitsch,R.;Pearce,C.;Katz,B.;Bringmann,G.;Feineis,D.;Taylor,D.L.;Tyrms,A.S.Isolation and characterization of the fungal metabolite 3-O-methylviridicatin as an inhibitor of tumour necrosis factor a-induced human immunodeficiency virus replication.Antiviral Chemistry & Chemotherapy 1998,9,149-155.
9.Xin,Z.;Fang,Y.;Zhu,T.;Duan,L.;Gu,Q.;Zhu,W.Antitumor components from sponge-derived fungus Penicillium auratiogriseum sp-19.Chin.J.Mar.Drugs.2006,25,1-6.
1.Nicolaou,K.C.;Jautelat,R.;Vassilikogiannakis,G.;Baran,P.S.;Simonsen,K.B.Studies towards Trichodimerol:Novel Cascade Reactions and Polycyclic Frameworks.Chem.Eur.J.1999,5,3651-3665.
2.Abe,N.;Sugimoto,O.;Tanji,K.;Hirota,A.Identification of the Quinol Metabolite “Sorbicillinol”,a Key Intermediate Postulated in Bisorbicillinoid Biosynthesis.J.Am.Chem.Soc.2000,122,12606-12607.
3.Cram,D.J.;Tishler,M.Mold Metabolites.I.Isolation of Several Compounds from Clinical Penicillin.J.Am.Chem.Soc.1948,70,4238-4239.
4.Cram D.J.Mold Metabolites.II.The Structure of Sorbicillin,a Pigment Produced by the Mold Penicillium nofafum.J.Am.Chem.Soc.1948,70,4240-4243.
5.Maskey,R.P.;Grün-WoIlny,I.;Laatsch,H.Sorbicillin Analogues and Related Dimeric Compounds from Penicillium notatum J.Nat.Prod.2005,68,865-870.
6.Abe,N.;Sugimoto,O.;Arakawa,T.;Tanji,K.I.;Hirota,A.Sorbicillinol,a key intermediate ofbisorbicillinoid biosynthesis in Trichoderma sp.USF-2690.Biosci.Biotech.Biochem.2001,65,2271-2279.
7.Abe,N.;Arakawa,T.;Yamamoto,K.;Hirota,A.Biosynthesis ofbisorbicillinoid in Trichoderma sp.USF-2690;evidence for the biosynthetic pathway,via sorbicillinol,of sorbicillin bisorbicillinol,bisorbibutenolide,and bisorbicillinolide.Biosci.Biotech.Biochem.2002,66,2090-2099.
8.Liu,W.Z.;Gu,Q.Q.;Zhu,W.M.;Cui,C.B.;Fan,G.T.Dihydrotrichodimerol and Tetrahydrotrichodimerol,Two New Bisorbicillinoids,from a Marine-derived Penicillium terrestre.J.Antibiot.2005,58,621-624.
9.Liu,W.Z.;Gu,Q.Q.;Zhu,W.M.;Cui,C.B.;Fan,G.T.Two New Benzoquinone Derivatives and Two New Bisorbicillinoids were Isolated from a Marine-derived Fungus Penicillium terrestre.J.Antibiot.2005,58,441-446.
10.Kontani,M.;Sakagami,Y.;Marumo,S.First β-1,6-Giucan Biosynthesis Inhibitor,Bisvertinolone Isoiated from Fungus,Acremonium stricturn and Its Absolute Stereochemistry.Tetrahedron Lett.1994,35,2577-2580.
11.Warr,G.A.;Veitch,J.A.;Walsh,A.W.;Hesler,G.A.;Pirnik,D.M.;Leet,J.E.;Lin,P.M.;Medina,I.A.;Mcbrien,K.D.;Forenza,S.;Clark,J.M.;Lam,K.S.182123,a Fungal Metabolite that Inhibits the Production of TNF-a by Macrophages and Monocytes.J. Antibiot.1996, 49, 234-240.
12. Koyama, N.; Ohshiro, T.; Tomoda, H.; Ohmura, S.; Fungal Isobisvertinol, a New Inhibitor of Lipid Droplet Accumulation in Mouse Macrophages. Org. Lett.2007, 9,425-428.
13. Andrade, R.; Ayer, I. A.; Mebe, P. P. The metabolites of Trichoderma longibrachiatum. Part1.1sblation of the metabolites and the structure of trichodimero. Can. J. Chem. 1992, 70,2526-2535.
14. Abe, N.; Murata, T.; Hirota, A. Novel DPPH radical scavengers, bisorbicillinol and demethyltrichodimerol, from a fungus. Biosci. Biotech. Biochem.1998, 62, 661-666.
15. Trifonov L. S., Hilpert H., Floersheim P., Dreiding A. S., Rast D. M.Skrivanova R., Hoesch L. Bisvertinols: a new group of dimeric vertimoids from Verticillium intertextum.Tetrahedron 1986, 42, 3157-3179.
16. Abe, N.; Arakawa, T.; Hirota, A. The biosynthesis of bisvertinolone: evidence for oxosorbicillinol as a direct precursor. Chem. Commun. 2002, 204-205.
17. Mossman, T.Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assay. J.Immunol.Meth.,1983, 65, 55-63.
1.Skehan,P.;Storeng,R.;Scudiero D.;Monks,A.;Mc Mahon,J.;Vistica,D.W.;Bokesch,H.;Kenney,S.;Boyd,M.R.New colorimetric cytotoxicity assay for anticancer drug screening.J.Natl.Cancer Inst.1990,82,1107-1112.
2.Voigh,W.Sulforhodamine B assay and chemosensitivity.Methods Mol.Med.2005,110,39-48.
3.Mossman,T.Rapid colorimetric assay for cellular growth and survival:application to proliferation and cytotoxicity assay.J.Immunol.Meth.1983,65,55-63.
4.Patricia,L.;Judson,M.D.;Linda,Van Le M.D.Flow cytometry.Oncology Update,1997,4,87-91.
1.Newman,D.J.;Gragg,M.C.Natural products as sources of new drugs over the last 25 years.J.Nat.Prod.2007,70,461-477.
2.Newman,D.J.;Gragg,M.C.;Snader,K.M.Natural products as sources of new drugs over the period 1981-2002.J.Nat.Prod.2003,66,1022-1037.
3.Pelish,H.E.;Westwood,N.J.;Feng,Y.;Kirchausen,T.;Shair,M.D.Use of biomimetic diversity-oriented synthesis to discover galanthamine-like molecules with biological properties beyond those of the natural product.J.Am.Chem.Soc.2001,123,6740-6741.
4.Spring,D.R.Diversity-oriented synthesis;a challenge for synthetic chemists.Org.Biomol.Chem.2003,1,3867-3870.
5.Burke,M.D.;Schreiber,S.L.A planning strategy for diversity-oriented synthesis.Angew.Chem.,Int.Ed.2004,43,46-58.
6.Zhonghong,G.;Reddy,P.T.;Quevillion,S.;Couve-Bonnaire,S.;Ayra,P.Stereocontrolled,solid phase synthesis of a 90 membered library of indoline alkaloid-like polycycles from an enantioenriched aminoindoline scaffold.Angew.Chem.,Int.Ed.2005,44,1366-1368.
7.Reayi,A.;Arya,P.Natural Product-like Chemical Space:Search for chemical dissectors of macromolecular interactions.Curr.Opin.Chem.Biol 2005,9,240-247.
8.Bergmann,W.;Feeney,R.J.Contributions to the study of marine products.ⅩⅩⅩⅡ.The nucleosides of sponges.I.J.Org.Chem.1951,16,981-987.
9.Bergmann,W.;Burke,D.C.Contributions to the study of marine products.XL.The nucleosides of sponges.Ⅳ.Spongosine.J.Org.Chem.1956,22,226-228.
10.Bergmann,W.;Stempien,M.F.Contributions to the study of marine products.XLIII.The nucleosides of sponges.V.The synthesis of spongosine.J.Org.Chem.1957,22,1575-1557.
11.Blunt,J.W.;Copp,B.R.;Hu,W.P.;Munro,M.H.G.;Northcote,P.T.;Prinsep,M.R.Marine natural products.Nat.Prod.Rep.2007,24,31-86.
12．王长云，耿美玉，管华诗．海洋药物研究进展与发展趋势．中国新药杂志，2005，14，278-282．
13.Molinski,T.F.;Dalisay,D.S.;Lievens,S.L.;Saludes,J.P.Drug development from marine natural products.Nature Reviews Drug Discovery 2009,8,69-85.
14.Newman,D.J.;Cragg,G.M.Marine natural products and related compounds in clinical and advanced preclinical trials.J.Nat.Prod.2004,67,1216-1238.
15.Feling,R.H.;Buchanan,G.O.;Mincer,T.J.;Kauffman,C.A.;Jensen,P.R.;Fenical,W.Salinosporamide A:a highly cytotoxic proteasome inhibitor from a novel microbial source,a marine bacterium of the new genus Salinospora.Angew.Chem.Intl.Ed.2003,42,355-357.
16.Gullo,V.P.;McAlpine,J.;Lam,K.S.;Baker,D.;Petersen,F.Drug discovery from natural products.J.Ind.Microbiol.Biotecnol.2006,33,523-531.
17.Rinehart,K.L.;Holt,T.G,.;Fregeau,N.L.;Strob,J.G.;Keifer,P.A.;Sun,F.;Li,L.H.;Martin,D.G.Ecteinascidin-743,Ecteinascidin-745,Ecteinascidin-759a,Ecteinascidin-759b,and Ecteinascidin-770 — potent antitumor agents from the Caribbean tunicate Ecteinascidia turbinata. J. Org. Chem. 1990, 55, 4512-4515.
18. Wright, A. E.; Forleo, D. A.; Gunawardana,G. P.; Gunasekera, S. P.; Koehn, F. E.; McConnell, O. J. Antitumor tetrahyrodisoquinoline alkaloids from the colonial ascidian Ecteinascidia turbinata. J.Org. Chem. 1990, 55, 4508-4512.
19. Corey, E. J.; Gin, D. Y.; Kania, R. S. Enantioselective total synthesis of ecteinascidin 743. J. Am. Chem. Soc. 1996,118, 9202-9203.
20. Sakai, R.; Rinehart, K. L.; Guan, Y.; Wang, A. H. Additional antitumor ecteinascidins from a Caribbean tunicate: crystal structures and activities in vivo. Proc. Nat. Acad. Sci. USA 1992, 89,11456-11460.
21. Cuevas, C; P(?)rez, M.; Martin, M. J. Synthesis of ecteinascidin ET-743 and Phthalascidin Pt-650 from cyanosafracin B. Org. Lett. 2000, 2, 2545-2548.
22. Pommier, Y.; Kohlhagen, G.; Bailly, C; Waring, M; Mazumder, A.; Kohn, K.W. DNA sequence-and structure- selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the Caribbean tunicate Ecteinascidia turbinata. Biochemistry 1996, 35, 13303-13309.
23. Zewail, F. M.; Hurley, L. H. Ecteinascidin 743: a minor groove alkylator that bends DNA toward the major groove. J. Med. Chem. 1999, 42, 2493-2497.
24. Takahashi, N.; Li, W. W.; Banerjee, D., Scotto, K. W.; Bertino, J. R. Sequence-dependent enhancement of cytotoxicity produced by ecteinascidin 743 (ET-743) with doxorubicin or paclitaxel in soft tissue sarcoma cells. Clin. Cancer Res. 2001, 7, 3251-3257.
25. Brain, E. G. Safety and efficacy of ET-743: the French experience. Anticancer Drugs 2002, 13,S11-S14.
26. Lau, L.; Supko, J. G.; Blaney, S.; Hershon, L.; Seibel, N.; Krailo, M.; Qu, W.; Malkin, D.; Jimeno,J.; Bernstein, M.; Baruchel, S. A phase I and pharmacokinetic study of ecteinascidin-743 (Yondelis) in children with refractory solid tumors. A children's oncology group study. Clin. Cancer Res.2005,11,672-677.
27. Jimeno, J.; Lopez Martin, J. A.; Ruiz Casado, A.; Izquierdo, M. A.; Scheuer, P.; Rinehart, K.Progress in the clinical development of new marine-derived anticancer compounds. Anticancer Drugs 2004, 15, 321-329.
28. Hirata, Y.; Uemura, D. Halichondrins-antitumor polyether macrolides from a marine sponge.Pure App.Chem. 1986, 58, 701-710.
29. Pettit, G. R.; Herald, C. L.; Boyd, M. R.; Leet, J. E.; Dufresne, C; Doubek, D. L.; Schmidt, J. M.;Cerny, R. L.; Hooper, J. N. A.; Rutzler, K. C. Antineoplastic agents. 219. Isolation and structure of the cell growth inhibitory constituents from the western Pacific marine sponge Axinella sp. J. Med.Chem. 1991, 34, 3339-3340.
30. Pettit, G. R.; Tan, R.; Gao, F.; Williams, M. D.; Doubeck, D. L.; Boyd, M. R.; Schmidt, J. M.;Chapuis, J. C; Hamel, E.; Bai, R.; Hooper, J. N. A.; Tackett, L. P. Isolation and structure of halistatin 1 from the eastern Indian Ocean marine sponge Phakellia carteri. J. Org. Chem. 1993, 58, 2538-2543.
31. Munro, M. H.; Blunt, J. W.; Dumdei, E. J.; Hickford, S. J.; Lill, R. E.; Li, S.; Battershill, C. N.;Duckworth, A. R.; Munro, M. H. G. The discovery and development of marine compounds with pharmaceutical potential. J. Biotechnol. 1999, 70, 15-25.
32. Bai, R. L.; Paull, K. D.; Herald, C. L.; Malspeis, L.; Pettit, G. R.; Hamel, E. Halichondrin B and homohalichondrin B, marine natural products binding in the vinca domain of tubulin. Discovery of tubulin-based mechanism of action by analysis of differential cytotoxicity data. J. Biol. Chem. 1991,266, 15882-15889.
33. Dabydeen, D. A.; Burnett, J. C; Bai, R.; Verdier-Pinard, P.; Hickford, S. J. H.; Pettit, G. R.; Blunt,J. W.; Munro, M. H. G.; Gussio, R.; Hamel, E. Comparison of the activities of the truncated halichondrin B analog NSC 707389 (E7389) with those of the parent compound and a proposed binding site on tubulin. Mol. Pharmacol. 2006, 70, 1866-1875.
34. Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y. Scola, P. M. Spero,D. M., Yoon, S. K. Total synthesis of halichondrin B and norhalichondrin B. J. Am. Chem. Soc.1992,114, 3162-3164.
35. Wang, Y.; Habgood, G. J.; Christ, W. J.; Kishi, Y.; Littlefield, B. A.; Yu, M. J. Structure-activity relationships of halichondrin B analogues: modifications at C30-C38. Bioorg. Med. Chem. Lett.2000,10,1029-1032.
36. Kuznetsov, G.; Towle, M. J.; Cheng, H.; Kawamura, T.; TenDyke, K.; Liu, D.; Kishi, Y.; Yu, M. J.;Littlefield, B. A. Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389. Cancer Res, 2004, 64,5760-5766.
37. Forero, J. B.; Heiskala, M. K.; Meneses, N.; Chandrawansa, K.; Fang, F.; Shapiro, G.; Fields, S. Z.;Silberman, S.; Vahdat, L. E7389, a novel anti-tubulin, in patients with refractory breast cancer. J.Clin. Oncol. 2006, 24, 653.
38. Pettit, G. R. The dolastatins. Fortschr. Chem. Org. Naturst. 1997, 70, 1-79.
39. Pettit, G. R.; Kamano, Y.; Herald, C. L.; Tuinman, A. A.; Boettner, F. E.; Kizu, H.; Schmidt, J. M.;Baczynskyj, L.; Tomer, K. B.; Bontems, R. J. The isolation and structure of a remarkable marine animal antineoplastic constituent- Dolastatin 10. J. Am. Chem. Soc.1987,109, 6883-6885.
40. Pettit, G. R. Progress in the discovery of biosynthetic anticancer drugs. J. Nat. Prod. 1996, 59,812-821.
41. Pettit, G. R.; Singh, S. B.; Hogan, F.; Lloyd-Williams, P.; Herald, D. L.; Burkett, D. D.; Clewlow, P.J. The absolute-configuration and synthesis of natural (-)-DoIastatin-10. J. Am. Chem. Soc. 1989,111,5463-5465.
42. Bai, R.; Pettit, G. R.; Hamel, E. Binding of dolastatin-10 to tubulin at a distinct site for peptide antimitotic agents near the exchangeable nucleotide and vinca alkaloid sites. J. Biol. Chem. 1990,265, 17141-17149.
43. Vaishampayan, H.; Glode, M.; Du, W.; Kraft, A.; Hudes, G.; Wright, J.; Hussain, M. Phase Ⅱ Study of Dolastatin-10 in Patients with Hormone- refractory Metastatic Prostate Adenocarcinoma.Clin.Canc.Res.2000,6,4205-4208.
44.Krug,L.M.;Miller,V.A.;Kalemkerian,G.P.;Kraut,M.J.;Ng,K.K.;Heelan,R.T.;Pizzo,B.A.;Perezl,W.;McClean,N.;Kris,M.G.Phase Ⅱ study of dolastatin-10 in patients with advanced non-small-cell lung cancer.Ann.Oncol.2000,11,227-228.
45.Margolin,K.;Longmate,J.;Synold,T.;Gandara,D.;Weber,J.;Gonzalez,R.;Johansen,M.;Newman,R.;Baratta,T.;Doroshow,J.Dolastatin-10 in metastatic melanoma:a phase Ⅱ and pharmokinetic trial of the California Cancer Consortium.Invest.New Drugs 2001,19,335-340.
46.Saad,E.D.;Kraut,E.H.;Hoff,P.M.;Moore,D.F.;Jr Jones,D.;Pazdur,R.;Abbruzzese,J.L.Phase II study of dolastatin-10 as first-line treatment for advanced colorectal cancer.Am.J.Clin.Oncol.2002,25,451-453.
47.von Mehren,M.;Balcerzak,S.P.~2;Kraft,A.S.;Edmonson,J.H.;Okuno,S.H.4;Davey,M.;McLaughlin,S.;Beard,M.T.;Rogatko,A.Phase Ⅱ trial of dolastatin-10,a novel anti-tubulin agent,in metastatic soft tissue sarcomas.Sarcoma 2004,8,107-111.
48.Perez,E.A.;Hillman,D.W.;Fishkin,P.;Krook,J.E.;Alberts,S.R.;Dakhil,S.R.Phase Ⅱ trial of dolastatin-10 in patients with advanced breast cancer.Invest.New Drugs 2005,23,257-261.
49.Kindler,H.L.;Tothy,P.K.;Wolff,R.;McCormack,R.A.;Abbruzzese,J.L.;Mani,S.;Wade-Oliver,K.T.;Vokes,E.E.Phase II trials of dolastatin-10 in advanced pancreaticobiliary cancers.Invest.New Drugs 2005,23,489-493.
50.de Jonge,M.J.A.;van der Gaast,A.;Planting,A.S.T.;van Doorn,L.;Lems,A.;Boot,I.;Wanders,J.;Satomi,M.;Verweij,J.Phase I and pharmacokinetic study of the dolastatin 10 analogue TZT-1027,given on days 1 and 8 of a 3-week cycle in patients with advanced solid tumors.Clin.Cancer Res.2005,11,3806-3813.
51.Kobayashi,M.;Natsume,T.;Tamaoki,S.;Watanabe,J.;Asano,H.;Mikami,T.;Miyasaka,K.;Miyazaki,K.;Gondo,M.;Sakakibara,K.;Tsukagoshi,S.;Antitumor activity ofTZT-1027,a novel dolastatin 10 derivative.Jpn.J.Cancer Res.1997,88,316-327.
52.Natsume,T.;Watanabe,J.;Tamaoki,S.;Fujio,N.;Miyasaka,K.;Kobayashi,M.Characterization of the interaction of TZT-1027,a potent antitumor agent,with tubulin.Jpn.J.Cancer Res.2000,91,737-747.
53．鲍光明，蒋晓慧，田敏卿，马亚平，袁厚群．目前处于临床研究的抗肿瘤活性天然产物．天然产物研究与开发2007，19，731-740．
54.Talpir,R.;Benayahu,Y.;Kashman,Y.;Pannell,L.;Schleyer,M.Hemiasterlin and geodiamolide TA:two new cytotoxic peptides from the marine sponge Hemiasterella minor (Kirkpatrick).Tetrahedron Lett.1994,35,4453-4456.
55.Coleman,J.E.;de Silva,E.D.;Kong,F.;Andersen,R.J.;Allen,T.M.Cytotoxic peptides from the marine sponge Cymbastela sp.Tetrahedron 1995,51,10653-10662.
56.Coleman,J.E.;Patrick,B.O.;Andersen,R.J.;Rettig,S.J.Hemiasterlin methyl ester.Acta Cryst.Sec.C 1996,C52,1525-1527.
57. Gamble, W. R.; Durso, N. A.; Fuller, R. W.; Westergaard, C. K.; Johnson, T. R.; Sackett, D.L.; Hamel, E.; Cardellina Ⅱ, J. H.; Boyd, M. R. Cytotoxic and tubulin-interactive hemiasterlins from Auletta sp. and Siphonochalina spp. sponges. Bioorg. Med. Chem. 1999, 7, 1611-1615.
58. Rinehart, K. L. Jr.; Gloer, J. B.; Cook, J. C; Mizsak, S. A.; Scahill, T. A. Structures of the didemnins, antiviral and cytotoxic depsipeptides from a Carribean tunicate. J. Am. Chem. Soc. 1981,103, 1857-1859.
59. Rinehart, K. L. Jr; Gloer, J. B.; Hughes, R. G. Jr; Renis, H. E.; McGovren, J. P.; Swynenberg, E. B.;Stringfellow, D. A.; Kuentzel, S. L.; Li, L. H. Didemnins: antiviral and antitumor depsipeptides from a Caribbean tunicate. Science 1981,212, 933-935.
60. Rinehart, K. L.; Kishore, V.; Nagarajan, S.; Lake, R. J.; Gloer, J. B.; Bozich, F. A.; Li, K.-M;Maleczka, R. E., Jr.; Todsen, T. L.; Munro, M. H. G; Sullins, D. W.; Sakai, R. Total synthesis of didemnins A, B, and C. J. Am. Chem. Soc. 1987, 109, 6856-6848.
61. Hossain, M. B.; van der Helm, D.; Antel, J.; Sheldrick, G. M.; Sanduja, S. K.; Weinheimer, A. J.Crystal and molecular structure of didemnin B, an antiviral and cytotoxic depsipeptide. Proc. Natl.Acad. Sci. USA 1988,55,4118-4122.
62. Meng, L.; Sin, N.; Crews, C. M. The antiproliferative agent didemnin B uncompetitively inhibits palmitoylprotein thioesterase. Biochemistry 1998, 37, 10488-10492.
63. Li, L. H.; Timmins, L. G.; Wallace, T. L.; Krueger, W. C; Prairie, M. D.; Im, W. B. Mechanism of action of didemnin B, a depsipeptide from the sea. Cancer Lett. 1984,23, 279-288.
64. Johnson, K. L.; Vaillant, F.; Lawen, A. Protein tyrosine kinase inhibitors prevent didemnin B-induced apoptosis in HL-60 cells. FEBS Lett. 1996, 383, 1-5.
65. Rinehart, K. L.; Lithgow-Bertelloni, A. M. Dehydrodidemnin B. 1991, WO9104985 (A1).
66. Sun, M. K.; Alkon, D. L. Dual effects of bryostatin-1 on spatial memory and depression. Eur. J.Pharm. Acol.2005, 512, 43-51.
67. Schaufelberger, D. E.; Koleck, M. P.; Beutler, J. A.; Vatakis, A. M.; Alvarado, A. B.; Andrews, P.;Marzo, L. V.; Muschik, G. M; Roach, J.; Ross, J. T. The large-scale isolation of bryostatin-1 from Bugula neritina following current good manufacturing practices. J. Nat. Prod. 1991, 54,1265-1270.
68. Rouhi, M. A. Supply issues complicate trek of chemicals from sea to market. Chem. Eng. News 1995, 73, 42-44.
69. Hennings, H.; Blumberg, P. M.; Pettit, G. R.; Herald, C. L.; Shores, R.; Yuspa, S.H. Bryostatin 1, an activator of protein kinase C, inhibits tumor promotion by phorbol esters in SENCAR mouse skia Carcinogenesis 1987, 8, 1343-1346.
70. Wender, P. A.; Cribbs, C. M.; Koehler, K. F.; Sharkey, N. A.; Herald, C. L.; Kamano, Y.;Pettit, G. R.; Blumberg, P. M. Modeling of the bryostatins to the phorbol ester pharmacophore on protein kinase C. Proc. Natl. Acad. Sci. USA 1988, 85, 7197-7201.
71. Moore, K. S.; Wehrli, S.; Roder, H.; Forrest, J. N. Jr.; McCrimmon, D.; Zasloff, M. Squalamine: an aminosterol antibiotic from the shark. Proc. Natl. Acad. Sci. USA 1993, 90, 1354-1358.
72. Pietras, R. J.; Weinberg, O. K. Antiangiogenic steroids in human cancer therapy. eCAM 2005, 2,49-57.
73. Hamann, M. T.; Scheuer, P. J. Kahalalide F: a bioactive depsipeptide from the Sacoglossan mollusk Elysia rufescens and the green alga Bryopsis sp. J. Am. Chem. Soc. 1993,115, 5825-5826.
74. Hamann, M. T.; Otto, C. S.; Scheuer, P. J.; Dunbar, D. C. Kahalalides: bioactive peptide from a marine mollusk Elysia rufescens and its algal diet Bryopsis sp. J. Org. Chem.1996, 61, 6594-6600.
75. Becerro, M. A.; Goetz, G.; Paul, V. J.; Scheuer, P. J. Chemical defenses of the sacoglossan mollusk Elysia rufescens and its host alga Bryopsis sp. J. Chem. Ecol. 2001,27, 2287-2299.
76. Goetz, G.; Yoshida, W. Y.; Scheuer, P. J. The absolute stereochemistry of kahalalide F.Tetrahedron 1999, 55,7739-7746.
77. Lopez-Macia,A.; Jimenez, J. C; Royo, M.; Giraet, E.; Albericio, F. Synthesis and structure determination of kahalalide F. J. Am. Chem. Soc. 2001,123, 11398-11401.
78. Bonnard, I.; Manzanares, I.; Rinehart, K. L. Stereochemistry of kahalalide F. J. Nat. Prod. 2003, 66,1466-1470.
79. Suarez, Y.; Gonzalez, L.; Cuadrado, A.; Berciano, M.; Lafarga, M.; Munoz, A. Kahalalide F, a new marine-derived compound, induces oncosis in human prostate and breast cancer cells. Mol. Cancer Ther. 2003, 2, 863-872.
80. Janmaat, M. L.; Rodriguez, J. A.; Jimeno, J.; Kruyt, F. A. E.; Giaccone, G. Kahalalide F induces necrosis-like cell death that involves depletion of ErbB3 and inhibition of Akt signaling. Mol. Pharmacol. 2005, 68, 502-510.
81. Gomez, S. G.; Bueren, J. A.; Faircloth, G. T.; Jimeno, J.; Albella, B. In vitro toxicity of three new antitumoral drugs (trabectedin, aplidin, and kahalalide F) on hematopoietic progenitors and stem cells. Exp. Hematol.2003, 31, 1104-1111.
82. Sparidans, R. W.; Stokvis, E.; Jimeno, J. M.; Lopez-Lazaro, L.; Schellens, J. H.; Beijnen, J. H.Chemical and enzymatic stability of a cyclic depsipeptide, the novel, marinederived, anti-cancer agent kahalalide F. Anticancer Drugs 2001,12,575-582.
83. Cuadros, R.; Montejo de Garcini, E.; Wandosell, F.; Faircloth, G.; Fernandez-Sousa, J. M.; Avila, J.The marine compound Spisulosine, and inhibitor of cell proliferation promotes the disassembly of actin stress fibers. Cancer Lett. 2000,152,23-29.
84. Hayakawa, Y.; Rovero, S.; Forni, G.; Smyth, M. J. a -Galactosylceramide (KRN7000) suppression of chemical- and oncogene-dependent carcinogenesis. Proc Natl Acad Sci USA 2003, 100,9464-9469.
85. Kem,W. R.; Abbott, B. C; Coates, R. M. Isolation and structure of a hoplonemertine toxin.Toxicon 1971,9,15-22.
86. de Fiebre, C. M.; Meyer, E. M.; Henry, J. C; Muraskin, S. I.; Kem, W. R.; Papke, R. L.Characterization of a family of anabaseine-derived compounds reveals that the 3-(4)-dimethylaminocinnamylidine derivative (DMAC) is a selective agonist at neuronal nicotinic α7/[~(125)I] a-bungarotoxin receptor subtypes. Mol. Pharmacol. 1995,47,164-171.
87. Wang, H. Y.; Lee, D. H. S.; Davis, C. B.; Shank, R. P. Amyloid peptide Abeta (1-42) binds selectively and with picomolar affinity to alpha 7 nicotinic acetylcholine receptor. J. Neurochem.2000,75, 1155-1161.
88. de Silva,E. D.; Scheuer, P. Manoalide, an antibiotic sesterterpenoid from the marine sponge Luffariella variabilis. Tetrahedron Lett. 1980,27, 1611-1614.
89. Deems, R. A.; Lombardo, D.; Morgan, D. P.; Mihelich, E. D.; Dennis, E. A. The inhibition of phospholipase A2 by manoalide and manoalide analogues. Biochim. Biophys. Acta 1987, 977,258-268.
90. Kernan, M. R.; Faulkner, D. J.; Jacobs, R. S. The luffariellins, novel antiinflammatory sesterterpenes of chemotaxonomic importance from the marine sponge Luffariella variabils. J. Org.Chem. 1987,52,3081-3083.
91. Burgoyne, D. L.; Andersen, R. J.; Allen, T. M. Contignasterol, a highly oxygenated steroid with the unnatural 14β configuration from the marine sponge Petrosia contignata thiele, J. Org. Chem. 1992,57, 525-528.
92. Takei, M.; Burgoyne, D. L.; Andersen, R. J. Effect of Contignasterol on Histamine Release Induced by Anti-Immunoglobulin E from Rat Peritoneal Mast Cells. J. Pharm. Sci. 1994, 83, 1234-1235.
93. Bramley, A. M.; Langlands, J. M.; Jones, A. K.; Burgoyne, D. L.; Li, Y.; Andersen, R. J.; Salari, H.Effects of IZP-94005 (contignasterol) on antigen-induced bronchial responsiveness in ovalbumin-sensitized guinea-pigs. Br. J. Pharmacol. 1995, 775, 1433-1438.
94. Feling, R. H.; Buchanan, G O.; Mincer, T. J. Kauffman, C. A.; Jensen, P. R. Fenical W Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus Salinospora. Angew. Chem. Intl. Ed. 2003, 42, 355-357.
95. Maldonado, L.; Fenical, W.; Goodfellow, M.; Jensen, P. R.; Ward, A. C. Salinispora gen nov., sp.nov., Salinispora arenicola sp. nov., and S. tropica sp. nov., obligate marine actinomycetes belonging to the family Micromonosporaceae. Internat. J. System. Appl. Microbiol. 2005, 55,1759-1766.
96. Chauhan, D.; Catley, L.; Li, G; Podar, K.; Hideshima, T.; Velankar, M.; Mitsiades ,C; Mitsiades,N.; Yasui, H.; Letai, A.; Ovaa, H.; Berkers, C; Nicholson, B.; Chao, T. H.; Neuteboom, S. T.;Richardson, P.; Palladino, M. A.; Anderson, K. C. A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell 2005,5,407-419.
97. Udwary, D. W.; Zeigler, L.; Asolkar, R. N.; Singan, V.; Lapidus, A.; Fenical, W.; Jensen, P. R.;Moore, B. S. Geome sequencing reveals complex secondary metabolome in the marine actinomycete Salinispora tropica. Proc. NatlAcad. Sci. USA 2007,104, 10376-10381.
98. Newman, D. J.; Hill, R. T. New drugs from marine microbes: the tide is turning. J. Ind. Microbiol.Biotechnol. 2006, 33, 539-544.
99. Hildebrand, M; Waggoner, L. E.; Liu, H.; Sudek, S.; Allen, S.; Anderson, C; Sherman, D. H.;Haygood, M. bryA: An unusual modular polyketide synthase gene from the uncultivated bacterial symbiont of the marine bryozoan Bugula neritina. Chem. Biol. 2004,11,1543-1552.
100. Sudek, S.; Lopanik, N. B.; Waggoner, L. E.; Hildebrand, M.; Anderson, C; Liu, H.; Patel, A.;Sherman, D. H.; Haygood, M. G. Identification of the putative bryostatin polyketide synthase gene cluster from "Candidatus Endobugula sertula", the uncultivated microbial symbiont from the marine bryozoan Bugula neritina. J. Nat. Prod. 2007, 70,61-74.