耐盐微生物的分离及两株耐盐真菌次级代谢产物的研究
|
摘要
耐盐微生物生存和培养于极端环境中,这种特殊的环境可能激活了该类微生物的某些沉默基因,从而产生结构特殊的蛋白,进而诱导出独特的生物代谢途径,使得其次级代谢产物结构新颖、种类繁多。因此,耐盐微生物是新结构活性化合物的重要来源。为了寻找耐盐微生物中的天才菌株(Talented strain)和结构新颖的活性化合物,本论文采用了化学与生物活性相结合的集成筛选方法,开展了生产抗肿瘤活性代谢产物的耐盐微生物的研究工作。内容包括:耐盐微生物的分离与抗肿瘤活性筛选;活性菌株的初步评价、天才菌株的获得及抗肿瘤活性成分的追踪分离;单体化合物的结构解析;单体化合物抗肿瘤活性的初步评价。
采用海虾生物致死法、K562细胞的流式细胞术筛选模型、抗氧化及抑菌试验筛选模型,以细胞周期抑制、细胞凋亡诱导,结合化学筛选,从19个分别采自内蒙古吉兰泰盐场和青海湖高盐环境的样品(其中13个泥样品,6个水样)中分离得到了174株耐盐微生物,从中筛选出3株活性菌,其中1株为天才菌株。
采用薄层色谱,硅胶柱色谱,Sephadex LH-20柱色谱,反相高效液相色谱等分离手段,通过解析波谱数据并结合理化常数阐明了从耐盐变色曲霉Aspergillus variecolor B-17中分得的49个化合物的结构: variecolortide A-C (1-3), variecolorins A-N (4-17), neoechinulin A (18), preechinulin (19), neoechinulin B (20), (21), dihydroxyisoechinulin (22), isoechinulin A (23), tardioxopiperazine A (24), tardioxopiperazine B (25), isoechinulin B (26), echinulin (27), Alkaloid E-7 (28), cryptoechinuline G (29), variecolorquinones B (30), variecolorquinones A (31), (2S)-2,3-dihydroxypropyl-1,6,8-trihydroxy-3-methyl-9,10-dioxoanthracene-2-carboxylate (32), emodin (33), physcion (34), questin (35), questinol (36), catenarin (38), erythroglaucin (39), rubrocristin (40), eurotinone (41), 2-methyleurotinone (42), flavoglaucin (43), aspergin (44), dihydroauroglaucin (45), 2-(1,1-dimethyl-2- propen-1-yl)-1H-Indole-3-carboxaldehyde (46), diisobutyl phthalate (47), butyrolactone I (48), halobutyrolactone A (49);从另一株耐盐微生物THW-18中分得的27个化合物的结构:halotolerantcerebroside A-C (50-52), cerebroside C (53), cerebroside D (54), (22E,24R)-3β,5α-Dihydroxy-23-methylergosta-7,22-dien-6-one(55), (22E,24R)-3β,5α-Dihydroxy-ergosta-7,22-dien-6-one (56), (22E,24R)-3β,5α,9α- trihydroxyergosta-7,22-diene-6-one (57), (22E,24R)-23-Methylergosta-7,22-diene- 3β,5α,9α-triol (58), cerevisterol (59), 3β,5α-dihydroxy-6β-methnoxyergosta-7,22- diene (60), ergosterol peroxide (61), ergosterol (62), demethylincisterol A3 (63), haloacetylaranotin A (64), bisdethiodi (methylthio) acetylaranotin (65), acetylaranotin (66), alterperylenol (67), dihydro-alterperylenol (68), altertoxin I (69), bis (2-ethylhexyl) phthalate (70), N-acetyltyramine (71), cyclo-(Tyr-Pro) (72), (15Z)-octadecenoic acid (73), (13Z)-hexadecenoic acid (74), benzoic acid (75), guanosine (76)。其中,生物碱类化合物1-17、醌类化合物30-31、丁内酯类化合物49、脑苷脂化合物50-52、甾醇类化合物56和含硫的环二肽类化合物64均为新化合物。
利用流式细胞术结合形态学检测、MTT和SRB法,对所分得的新结构单体化合物的体外抗肿瘤活性进行了初步评价。结果表明,新化合物1-3对K562细胞有弱的增殖抑制活性;新化合物4-17对P388、A-549、HL-60和BEL-7402细胞都具有较弱的细胞毒活性;新化合物30对多种人癌细胞及哺乳动物癌细胞有较强的细胞增殖抑制活性;新化合物31对人肺癌A-549细胞具有较强的细胞毒活性;新甾醇类化合物56对HL-60有一定细胞增殖抑制活性。在自由基清除试验中,新化合物17显示较强的自由基清除活性;新化合物1-14和31显示中等强度的自由基清除活性;新化合物64显示弱的自由基清除活性;已知化合物41-45显示较强的自由基清除活性;化合物18、20、22、23、26、28、29、32-40显示中等强度的自由基清除活性;67-69显示弱的自由基清除活性。
综上,本文经活性筛选从174株耐盐微生物中获得3株活性菌,其中1株为“Talented strain”;通过对2株“Talented strain”中次级代谢产物的系统研究,共分离鉴定了76个化合物,其中新化合物25个。首次发现了3个结构新颖的蒽醌与二酮哌嗪类化合物聚合体新骨架化合物,其它新化合物中还包含3个分子中含有卤素的化合物。生物活性测试表明,这些新化合物均有一定程度的体外抗肿瘤活性。上述研究为抗肿瘤新药研究提供了微生物资源和结构新颖的筛选化合物,也为设计合成新的卤代药物提供了思路。
Haltolerant microorganisms have been considered an important source of bioactive leading compounds, due to their unique living environment. A study on two“talented strains”of halotolerant microorganisms was carried out to investigate the potential anti-tumor compounds. Studies include screening for microbial strains with antitumor acitvities, fermentation studies, bioassay-guided fractionation, structural elucidation, and preliminary evaluation for anti-tumor activities of new compounds.
Using MTT or SRB methods, one halotolerant“talented strains”were screened out of one hundred and seventy four halotolerant microorganisms isolated from hypersaline samples, on the bioassay of K562 cell lines. Two“talented strains”were chosen based on the result of re-screening combining with HPLC and TLC chemical analysis. After choosing appropriate fermentation condition, these strains were fermented, respectively. The whole broths were extracted with ethyl acetate to give ferment extracts, which were subjected to silica gel column chromatography, Sephadex LH-20 and HPLC by bioassay-guided fractionation, respectively. Seventy six compounds were isolated from the two strains. Forty nine compounds (1-49) were isolated from fungus B-17 (Aspergillus variecolor) and twenty seven compounds (50-76) were isolated from fungus THW-18.
By means of modern spectral analysis (UV, IR, NMR, MS, CD, X-Ray) and physico-chemical properties, the structures (see Fig. 1) of seventy six pure compounds were respectively determined. Among them there are twenty five new compounds, including three novel alkaloids, variecolortides A-C (1-3), which share an unprecedented‘spiro-anthronopyranoid diketopiperazine’structure and were deduced by single-crystal X-ray analysis; fourteen new enchinulin variecolorins A-N (4-17); two novel quinone type compounds variecolorquinones A-B (30-31), a new butyrolactone type compound halobutyrolactone A (49); three new cerebroside halotolerantcerebroside A-C (50-52), one new steroide (22E,24R)-3β,5α- Dihydroxy- 23-methylergosta-7,22-dien-6-one (56) and one new diketopiperazine type compound haloacetylaranotin A (64).
These compounds were evaluated for their cytotoxicities against several cancer cell lines such as HL-60, P388, K562, etc, by the MTT or SRB method. The results indicated that all of the new compounds showed cytotoxicities in certain extent. Among them, variecolortides A-C (1-3) showed week bioactivity against K562 (IC50 = 63, 84 and 91μM respectively), variecolorquinones B have significant cytotoxicities against P388 and HL-60 cells (IC50 = 3.7 and 1.3μM respectively) and variecolorquinones B selectively inhibited the proliferation of A-549 cell (IC50 = 3.0μM). Compounds 4-17, 50-52 and 64 exhibited weak cytotoxicities. In addition, all the compounds were evaluated for their DPPH scavenging activity. The results indicated that compounds 1-14, 17-18, 20, 22, 23, 26, 28, 29, 31-45, 67-69 showed antioxidative activity in certain extent.
Summarily, this work obtained one“talented strains”from halotolerant microorganisms and seventy six compounds from two fungal strains. Among them, twenty four compounds were identified new. Studies mentioned above provided novel structures for searching leading antitumor compounds and strain resources of great value for further study and development of halotolerant microorganism.
采用海虾生物致死法、K562细胞的流式细胞术筛选模型、抗氧化及抑菌试验筛选模型,以细胞周期抑制、细胞凋亡诱导,结合化学筛选,从19个分别采自内蒙古吉兰泰盐场和青海湖高盐环境的样品(其中13个泥样品,6个水样)中分离得到了174株耐盐微生物,从中筛选出3株活性菌,其中1株为天才菌株。
采用薄层色谱,硅胶柱色谱,Sephadex LH-20柱色谱,反相高效液相色谱等分离手段,通过解析波谱数据并结合理化常数阐明了从耐盐变色曲霉Aspergillus variecolor B-17中分得的49个化合物的结构: variecolortide A-C (1-3), variecolorins A-N (4-17), neoechinulin A (18), preechinulin (19), neoechinulin B (20), (21), dihydroxyisoechinulin (22), isoechinulin A (23), tardioxopiperazine A (24), tardioxopiperazine B (25), isoechinulin B (26), echinulin (27), Alkaloid E-7 (28), cryptoechinuline G (29), variecolorquinones B (30), variecolorquinones A (31), (2S)-2,3-dihydroxypropyl-1,6,8-trihydroxy-3-methyl-9,10-dioxoanthracene-2-carboxylate (32), emodin (33), physcion (34), questin (35), questinol (36), catenarin (38), erythroglaucin (39), rubrocristin (40), eurotinone (41), 2-methyleurotinone (42), flavoglaucin (43), aspergin (44), dihydroauroglaucin (45), 2-(1,1-dimethyl-2- propen-1-yl)-1H-Indole-3-carboxaldehyde (46), diisobutyl phthalate (47), butyrolactone I (48), halobutyrolactone A (49);从另一株耐盐微生物THW-18中分得的27个化合物的结构:halotolerantcerebroside A-C (50-52), cerebroside C (53), cerebroside D (54), (22E,24R)-3β,5α-Dihydroxy-23-methylergosta-7,22-dien-6-one(55), (22E,24R)-3β,5α-Dihydroxy-ergosta-7,22-dien-6-one (56), (22E,24R)-3β,5α,9α- trihydroxyergosta-7,22-diene-6-one (57), (22E,24R)-23-Methylergosta-7,22-diene- 3β,5α,9α-triol (58), cerevisterol (59), 3β,5α-dihydroxy-6β-methnoxyergosta-7,22- diene (60), ergosterol peroxide (61), ergosterol (62), demethylincisterol A3 (63), haloacetylaranotin A (64), bisdethiodi (methylthio) acetylaranotin (65), acetylaranotin (66), alterperylenol (67), dihydro-alterperylenol (68), altertoxin I (69), bis (2-ethylhexyl) phthalate (70), N-acetyltyramine (71), cyclo-(Tyr-Pro) (72), (15Z)-octadecenoic acid (73), (13Z)-hexadecenoic acid (74), benzoic acid (75), guanosine (76)。其中,生物碱类化合物1-17、醌类化合物30-31、丁内酯类化合物49、脑苷脂化合物50-52、甾醇类化合物56和含硫的环二肽类化合物64均为新化合物。
利用流式细胞术结合形态学检测、MTT和SRB法,对所分得的新结构单体化合物的体外抗肿瘤活性进行了初步评价。结果表明,新化合物1-3对K562细胞有弱的增殖抑制活性;新化合物4-17对P388、A-549、HL-60和BEL-7402细胞都具有较弱的细胞毒活性;新化合物30对多种人癌细胞及哺乳动物癌细胞有较强的细胞增殖抑制活性;新化合物31对人肺癌A-549细胞具有较强的细胞毒活性;新甾醇类化合物56对HL-60有一定细胞增殖抑制活性。在自由基清除试验中,新化合物17显示较强的自由基清除活性;新化合物1-14和31显示中等强度的自由基清除活性;新化合物64显示弱的自由基清除活性;已知化合物41-45显示较强的自由基清除活性;化合物18、20、22、23、26、28、29、32-40显示中等强度的自由基清除活性;67-69显示弱的自由基清除活性。
综上,本文经活性筛选从174株耐盐微生物中获得3株活性菌,其中1株为“Talented strain”;通过对2株“Talented strain”中次级代谢产物的系统研究,共分离鉴定了76个化合物,其中新化合物25个。首次发现了3个结构新颖的蒽醌与二酮哌嗪类化合物聚合体新骨架化合物,其它新化合物中还包含3个分子中含有卤素的化合物。生物活性测试表明,这些新化合物均有一定程度的体外抗肿瘤活性。上述研究为抗肿瘤新药研究提供了微生物资源和结构新颖的筛选化合物,也为设计合成新的卤代药物提供了思路。
Haltolerant microorganisms have been considered an important source of bioactive leading compounds, due to their unique living environment. A study on two“talented strains”of halotolerant microorganisms was carried out to investigate the potential anti-tumor compounds. Studies include screening for microbial strains with antitumor acitvities, fermentation studies, bioassay-guided fractionation, structural elucidation, and preliminary evaluation for anti-tumor activities of new compounds.
Using MTT or SRB methods, one halotolerant“talented strains”were screened out of one hundred and seventy four halotolerant microorganisms isolated from hypersaline samples, on the bioassay of K562 cell lines. Two“talented strains”were chosen based on the result of re-screening combining with HPLC and TLC chemical analysis. After choosing appropriate fermentation condition, these strains were fermented, respectively. The whole broths were extracted with ethyl acetate to give ferment extracts, which were subjected to silica gel column chromatography, Sephadex LH-20 and HPLC by bioassay-guided fractionation, respectively. Seventy six compounds were isolated from the two strains. Forty nine compounds (1-49) were isolated from fungus B-17 (Aspergillus variecolor) and twenty seven compounds (50-76) were isolated from fungus THW-18.
By means of modern spectral analysis (UV, IR, NMR, MS, CD, X-Ray) and physico-chemical properties, the structures (see Fig. 1) of seventy six pure compounds were respectively determined. Among them there are twenty five new compounds, including three novel alkaloids, variecolortides A-C (1-3), which share an unprecedented‘spiro-anthronopyranoid diketopiperazine’structure and were deduced by single-crystal X-ray analysis; fourteen new enchinulin variecolorins A-N (4-17); two novel quinone type compounds variecolorquinones A-B (30-31), a new butyrolactone type compound halobutyrolactone A (49); three new cerebroside halotolerantcerebroside A-C (50-52), one new steroide (22E,24R)-3β,5α- Dihydroxy- 23-methylergosta-7,22-dien-6-one (56) and one new diketopiperazine type compound haloacetylaranotin A (64).
These compounds were evaluated for their cytotoxicities against several cancer cell lines such as HL-60, P388, K562, etc, by the MTT or SRB method. The results indicated that all of the new compounds showed cytotoxicities in certain extent. Among them, variecolortides A-C (1-3) showed week bioactivity against K562 (IC50 = 63, 84 and 91μM respectively), variecolorquinones B have significant cytotoxicities against P388 and HL-60 cells (IC50 = 3.7 and 1.3μM respectively) and variecolorquinones B selectively inhibited the proliferation of A-549 cell (IC50 = 3.0μM). Compounds 4-17, 50-52 and 64 exhibited weak cytotoxicities. In addition, all the compounds were evaluated for their DPPH scavenging activity. The results indicated that compounds 1-14, 17-18, 20, 22, 23, 26, 28, 29, 31-45, 67-69 showed antioxidative activity in certain extent.
Summarily, this work obtained one“talented strains”from halotolerant microorganisms and seventy six compounds from two fungal strains. Among them, twenty four compounds were identified new. Studies mentioned above provided novel structures for searching leading antitumor compounds and strain resources of great value for further study and development of halotolerant microorganism.
引文
1. Hasan H A H. Studies on toxicogenic fungi in roasted foodstuff (salted seed) and halotolerant activity of emodin-producing Aspergillus wentii. Folia Microbiol. 1998, 43: 383-391.
2. Khmel I A. Regulation of expression of bacterial genes in the absence of active cell growth. Russ. J. Genet. 2005, 41: 968-984.
3. Schlictman D, Kubo M, Shankar S, et al. Regulation of nucleoside diphosphate kinase and secretable virulence factors in Pseudomonas aeruginosa: roles of algR2 and algH. J. Bacteriol. 1995, 177: 2469-2474.
4. Tamburini E, Mastromei G. Do bacterial cryptic genes really exist? Res. Microbiol. 2000, 151: 179-182.
5. Koch A L. Genetic response of microbes to extreme challenges. J. Theor. Biol. 1993, 160: 1-21.
6. Mejanelle L, Lopez J F, Gunde-Cimerman N, Grimalt J O. Ergosterol biosynthesis in novel melanized fungi from hypersaline environments. J. Lipid Res. 2001, 42: 352-358.
7. Werner E G M, Heinz C S, Matthias W, et al. Isabel M. M. Traditional and Modern Biomedical Prospecting: Part II - the Benefits. eCAM, 2004, 1(2): 133-144
8. Werner E G M, Renato B, Heinz C S, et al. Traditional and Modern Biomedical Prospecting: Part I - the History, Sustainable Exploitation of Biodiversity (Sponges and Invertebrates) in the Adriatic Sea in Rovinj (Croatia). eCAM, 2004, 1(1): 71-82.
9.肖建球。海洋微生物代谢物抗肿瘤活性的研究进展。中医药导报,2005, 11(7): 95-96.
10. Larsen T O, Smedsgaard J, Nielsen K F, et al. Phenotypic taxonomy and metabolite profiling in microbial drug discovery. Nat Prod Rep, 2005, 22, 672-695
[1] Solis P N, Wright C W, Anderson M M, et al. A microwell cytotoxicity assay using Artemia salina (brine shrimp). Planta Med., 1993, 59(3): 250-252.
[2] Meyer B N, Ferrigni N R, Putnam J E, et al. Brine Shrimp: A convenient general bioassay for active plant constituents. Planta Med., 1982, 45(1): 31-34.
[3]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(6): 804-809.
[4]杰利·L·麦克劳林,顾哲明.两种建议的抗肿瘤活性初筛方法.中国中药杂志, 1997, 22(10): 617-619.
[5] Yun B S, Lee I K, Yoo I D, et al. Two p-terphenyls from mushroom Paxillus panuoides with free radical scavenging activity. J. Micobiol. Biotechnol., 2000, 10: 233-237.
[6] Cui C B, Zhao Q C, Cai B, et al. Two new and four known polyphenolics obtained as new cell-cycle inhibitors from Rubus aleaefolius Poir. J. Asian Nat. Prod. Res., 2002, 4 (4): 243-252.
[7]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筛选.青岛海洋大学学报. 2002, 32(123), 123-126.
[1] Marchelli R, Dossena A, Pochini A, et al. The structures of five new didehydropeptides related to neoechinulin, isolated from Aspergillus amstelodami. J. Chem. Soc. PerkinⅠ, 1977:713-717
[2] Wakulinski W, Kachlicki P, Sobiczewski P, et al. Catenarin production by isolates of Pyrenophora tritici-repentis (Died.) Drechsler and its antimicrobial activity. J. Phytopathol. 2003, 151: 74-79.
[3] Li Y, Li X, Kang J S, et al. New radical scavenging and ultraviolet-A protecting prenylated dioxopiperazine alkaloid related to isoechinulin A from a marine isolate of the fungus Aspergillus. J. Antibiot. 2004, 57: 337–340.
[4] Barbetta M, Casnati G., Pochini A, et al. Neoechinuline: a new indole metabolite from Aspergillus amstelodami. Tetrahedron Lett. 1969, 51: 4457-4460.
[5] Gatti G., Fuganti C. Carbon-13 NMR spectra of echinuline and related compounds. J. Chem. Res. Synop. 1979, 11: 366-367.
[6] Nagasawa H, Isogai A, Suzuki A, et al. Structures of isoechinulins A, B and C, new indole metabolites from Aspergillus ruber. Tetrahedron Lett. 1976, 19: 1601-1604.
[7] 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(8): 1759-1763.
[8]范国涛。海洋来源真菌KLEB-07、H2-02和WZ4-F22次级代谢产物抗肿瘤活性成分研究。中国海洋大学2005届硕士论文。
[9] Quilico A, Panizzi L. Chemical investigations of Aspergillus echinulatus. I. Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen. 1943, 76B: 348-358.
[10] Quilico A, Cardani C. The diffusion of echinulin in molds of the group Aspergillus glaucus. Atti accad. nazl. Lincei, Rend. classesci. fis., mat. e nat. 1950, 9: 220-228.
[11] Kitamura J, Kurimoto U, Yokoyama M. Metabolic products of Aspergillus chevalieri. Yakugaku Zasshi 1956, 76: 972-973.
[12] Fujimoto H, Fujimaki T, Okuyama E, et al. Immunomodulatory constituents from anascomycete, Microascus tardifaciens. Chem. Pharm. Bull. 1999, 47(10): 1426-1432.
[13] Yagi R, Doi M. Isolation of an antioxidative substance produced by Aspergillus repens. Biosci. Biotechnol. Biochem., 1999, 63: 932-933.
[14] Dossena A, Marchelli R, Pochini A. New metabolites of Aspergillus amstelodami related to the biogenesis of neoechinulin. J. Chem. Soc. Chem. Comm., 1974: 771-772.
[15] Houghton E, Saxton J E. Echinuluin series.Ⅱ. Synthesis of (+)-alanyl- tryptophan anhydride and L-alanyl-2-(1,1-dimethylallyl)tryptophan anhydride. J. Chem. Soc. [section] C: Organic, 1969(6): 1003-1012
[16] Stipanovic R D, Schroeder H. Preechinulin, a metabolite of Aspergillus chevalieri. Transactions of the British Mycological Society, 1976, 66: 178-179
[17] Takashi H, Kouzou N, Yuichi H. A new metabolite, L-alanyl-L-tryptophan anhydride from Aspergillus chevalieri. Agr. Boil. Chem., 1976, 40 (12): 2487
[18] Nakashima Ruka, Slater, G P. Configuration of echinulin. Tetrahedron Letters, 1967, 45: 4433-4436.
[19] Stipanovic R D, Schroeder H W, Hein H J. Identification of D-valyl-L-tryptophan anhydride from Aspergillus chevalieri. Lloydia, 1976, 39(2-3): 158-159.
[20] Nakashima R, Slater G P. Configuration of echinulin. II. Optical rotatory dispersion of echinulin, hydroechinulin, and the stereoisomeric 3-methyl-6-(incolyl-3-methyl)piperazine- 2,5-diones. Can. J. Chem., 1969, 47 (11): 2069-2074.
[21] Birch A J, Blance G E, David S, et al. J. Chem. Soc., 1961: 3128-3131
[22] Talapatra S K, Mandal S K, Bhaumik A, et al. Echinulin, a novel cyclic dipeptide carrying a triprenylated indole moiety from an Anacardiaceae, a Cucurbitaceae and two Orchidaceae plants: detailed high resolution 2D-NMR and mass spectral studies. Journal of the Indian Chemical Society, 2001, 78(10-12): 773-777
[23] Inoue S, Murata J, Takamatsu N, et al. Synthetic studies on echinulin and related natural products. V. Isolation, structure and synthesis of echinulin-neoechinulin type alkaloids isolated from Aspergillus amstelodami. Yakugaku Zasshi. 1977, 97(5): 576-581.
[24] Gatti G, Cardillo R, Fuganti C. Molecular structure of cryptoechinuline G, an isoprenylated dehydrotryptophan metabolite isolated from Aspergillus ruber. Tetrahedron Lett. 1978, 29: 2605-2606.
[25] Segaw A, Miyaichi Y, Tomimori T, et al. Studieson nepalese crude drugs XXV. Phenolic constituents of theleaves of Didymocarpus leucocalyx C. B. Clarke (Gesnerriaceae). Chem Pharm Bull. 1999,47: 1404–1411
[26]许颂,梁华清.刺人参的蒽醌成分研究.中草药, 1998, 29(4): 222-223.
[27] Alemayehu G, Abegaz B, Snatzke G, et al. Bianthraquinone alkaloid from Cassia floribunda. Phytochemistry, 1988, 27 (10): 3255-3258
[28] Coskun M, Tanker N, Sakushima A, et al. An anthraquinone glycoside from Rhamnus pallasii. Phytochemistry, 1984, 23 (7): 1485-1487.
[29] Kalidhar S B. Structural elucidation in anthraquinones using 1H NMR glycosylation and alkylation shifts. Phytochemstry, 1989, 28 (12): 3459-3463
[30]李建北,林茂.何首乌化学成分的研究.中草药, 1993, 24 (3): 115-118
[31] Anke H, Kolthoum I, Laatsch H. Metabolic products of microorganisms. 192. The anthraquinones of the Aspergillus glaucus group. II. Biological activity. Arch Microbiol, 1980, 126: 231–236
[32] Eder C, Kogler H, Toti L. Preparation of eurotinone, a KDR kinase inhibitor from Eurotium echinulatum (DSM 13872). 2003, WO 2003002549.
[33] Hamasaki T, Kimura Y, Hatsuda Y, et al. Structure of a new metabolite, dihydroauroglaucin, produced by Aspergillus chevalieri. Agric. Biol. Chem. 1981, 45(1): 313-314.
[34] Hamasaki T, Fukunaga M, Kimura Y, et al. Isolation and structures of two new metabolites from Aspergillus ruber. Agric. Biol. Chem. 1980, 44(7): 1685-1687.
[35] Itokawa H, Akita Y, Yamazaki M. Indole derivatives isolated from the oil cakes of Camellia seeds. Relation to the components of the fungus infecting the oil cakes. Yakugaku Zasshi 1973, 93(9): 1251-1252.
[36] Nitta K, Fujita N, Yoshimura T, et al. Metabolic products of Aspergillus terreus. IX. Biosynthesis of butyrolactone derivatives isolated from strains IFO 8835 and 4100. Chem. Pharm. Bull. 1983, 31(5): 1528-1533.
[37] Niu X, Dahse H, Menzel K, et al. Butyrolactone I derivatives from Aspergillus terreus carrying an unusual sulfate moiety. J. Nat. Prod. (release online).
[38] Allen C M Jr. Biosynthesis of echinulin. Isoprenylation of cyclo-L-alanyl-L-tryptophanyl. Biochemistry, 1972, 11 (11): 2154-2160。
[39] Allen C M Jr. Monoisoprenylated cyclo-L-alanyl-L-tryptophanyl. A biosynthetic precursor of echinulin. J. Am. Chem. Soc., 1973, 95 (7): 2386-2387。
[40] Li Y, Li X, Kim S K, et al. Golmaenone, a new diketopiperazine alkaloid from the marine-derived fungus Aspergillus sp.. Chem. Pharm. Bull., 2004, 52 (3): 375-376
[41] Ravikanth V, Niranjan Reddy V L, Ramesh P, et al. An immunosuppressive tryptophan-derived alkaloid from Lepidagathis cristata. Phytochemistry, 2001, 58: 1263-1266
[42] Yukihiro I, Kyozo M, Takashi H. Metabolites of Eurotium species, their antioxidative properties and synergism with tocopherol. Journal of Food Science, 1985, 50 (6): 1742-1744
[43] Kiyoshi K, Kazuo H, Teruhiko N, et al. Inhibition of mitochondrial electron transport system by flavoglaucin from Eurotium chevalieri. II. The interaction with complex III. Mycotoxins, 1986, 24: 13-18.
[44] Kiyoshi K, Hideki M, Jiro K. The uncoupling effect of flavoglaucin, a quinol pigment from Aspergillus chevalieri (Mangin), on mitochondrial respiration. Toxicology Letters, 1983, 19 (3): 321-325
[1] Zhan Z J, Yue J M. New glycophingolipids from the fungus Catathelasma ventricosa. J. Nat. Prod., 2003, 66: 1013-1016
[2] Sitrin R D, Chan G, Dingerdissen J, et al. Isolation and structure determination of Pachybasium cerebrosides which potentiate the antifungal activity of aculeacin. J. Antibiotic., 1988, 41 (4): 469-480
[3] Keusgen M, Yu C M, Curtis J M, et al. A cerebroside from the marine fungus Microsphaeropsis olivacea (bonord) H?hn. Biochemical Systematics and Ecology, 1996, 24 (5): 465-468。
[4] Walker T E, London R E, Whaley T W, et al. Carbon-13 nuclear magnetic resonance spectroscopy of [1-13C] enriched monosaccharides. Signal assignments and orientational dependence of geminal and vicinal carbon-carbon and carbon-hydrogen spin-spin coupling constants. J. Am. Chem. Soc., 1976, 98 (19): 5807-5813
[5] Kang S S, Kim J S, Xu Y N, et al. Isolation of a new cerebroside from the root bark of Aralia elata. J. Nat.Prod., 1999, 62: 1059-1060
[6] Qi J H, Ojika M, Sakagami Y. Termitomycesphins A-D, novel neuritogenic cerebrosides from the edible Chinese mushroom Termitomyces albuminosus. Tetrahedron, 2000, 56: 5835-5841
[7] Jin W Z, Rinehart K L, Jares-Erijman E A. Ophidiacerebrosides: cytotoxic glycosphingolipids containing a novel sphingosine from a sea star. J. Org. Chem., 1994, 59: 144-147.
[8] Kim S Y, Choi Y H, Huh H, et al. New antihepatotoxic cerebroside from Lycium chinense fruits. J. Nat. Prod., 1997, 60: 274-276。
[9] Sugimura H, Yoshida K. Diastereoselective reduction of chiralβ,γ-unsaturated a-Oxo esters. Asymmetric synthesis of thefatty acid moiety of symbioramide. J. Org. Chem., 1993, 58: 4484-4486
[10] Takanami T, Tokoro H, Kato D, et al. Chemo-enzymatic short-step total synthesis of symbioramide. Tetrahedron Lett., 2005, 46: 3291–3295
[11] Shu R G, Wang F W, Yang Y M, et al. Antibacterial and Xanthine Oxidase InhibitoryCerebrosides from Fusarium sp. IFB-121, an Endophytic Fungus in Quercus variabilis Lipids, 2004, 39 (7): 667-673.
[12] Hora J, Labler L, Kasal A, et al. Steroids. CIII. Molting deficiencies produced by some sterol derivatives in an insect (Pyrrhocoris apterus). Steroids, 1966, 8(6): 887-914.
[13] Valisolalao J, Luu B, Ourisson G. Chemical and biochemical study of Chinese drugs. Part VIII. Cytotoxic steroids from Polyporus versicolor. Tetrahedron, 1983, 39(17): 2779-2785.
[14] Yaoita Y, Endo M, Tani Y, et al. Sterol constituents from seven mushrooms. Chem. Pharm. Bull. 1999, 47(6): 847-851.
[15] Aiello A, Ciminiello P, Fattorusso E, et al. 3β,5α-Dihydroxy-6β-methoxy- cholest-7-enes from the marine sponge Spongia agaricina. J. Nat. Prod., 1988, 51 (5): 999-1002
[16] Kawagishi H, Katsumi R, Sazawa T, et al. Cytotoxic steroids from the mushroom Agaricus blazei. Phytochemistry, 1988, 27 (9): 2777-2779
[17] Fujimoto Y, Yamada T, Ikekawa N. Pyridine-induced deshielding of 4-methylene protons for the determination of C-6 stereochemistry of sterols having a 5α,6-diol moiety. Revision of the stereochemistry of marine sterol isolated from a sponge, Dysidea sp. Chem. Pharm. Bull., 1985, 33 (8): 3129-3133
[18]高锦明,董泽军,刘吉开.蓝黄红姑的化学成分.云南植物研究,2000,22(1): 85-89
[19] Takaishi Y, Uda M, Ohashi T, et al. Glycosides of ergosterol derivatives from Hericum erinacens. Phytochemstry, 1991, 30 (12): 4117-4120
[20] De Riccardis F, Spinella A, Izzo I, et al. Synthesis of (17R)-17-methylincisterol, a highly degraded marine steroid. Tetrahedron Lett. 1995, 36(24): 4303-4306.
[21] Mansoor T A, Hong J, Lee C O, et al. Cytotoxic sterol derivatives from a marine sponge Homaxinella sp. J. Nat. Prod. 2005, 68(3): 331-336.
[22] Rahman R, Safe S, Taylor A. Separation of polythiadioxopiperazine antibiotics by thin-layer chromatography. J. Chromatography, 1970, 53(3): 592-594
[23] Rastetter W H, Chancellor T, Richard T J. Biogenesis of epidithiadioxopiperazines. Nucleophilic additions to benzene oxide and sym-oxepin oxide. J. Org. Chem. 1982, 47(8): 1509-1512.
[24] Okuno T, Natsume I, Sawai K, et al. Structure of antifungal and phytotoxic pigments produced by Alternaria species. Tetrahedron Lett. 1983, 24(50): 5653-5656.
[25] Arnone A, Assante G, Caronna T, et al. Comparative evaluation of photodynamic efficiency of some natural quinonoid fungal toxins. Phytochemistry 1988, 27(6): 1669-1674.
[26] Stinson E E, Osman S F, Pfeffer P E. Structure of Altertoxin I, a mycotoxin from Alternaria. J. Org. Chem. 1982, 47(21): 4110-4113
[27]李想,姚燕华,郑毅男,等。红树林植物海漆的化学成分(Ⅰ).中国天然药物, 2006, 4(3): 188-191。
[28]胡海峰,朱宝泉,龚炳.微生物来源的胆固醇生物合成醇抑制剂研究:抗生素SIPI-8926-111的研究.中国医药工业杂志, 1995, 26 (11), 484-486.
[29]熊江,周俊,戴好富.多蕊商陆的化学成分.云南植物研究, 2002, 24: 401-403
[30] Sebedio J L, Bonpunt A, Grandgirard A, et al. Deep fat frying of frozen prefried french fries: influence of the amount of linolenic acid in the frying medium. J. Agr. Food Chem 1990, 38(9): 1862-1867.
[31]丁智慧,丁靖垲,易元芬.细梗香草的挥发油成分.云南植物研究. 1989, 11(2): 209-214
[32] Cotteret J, Lagrange A. Hair dyeing compositions comprising a tertiary p-phenylenediamine with a pyrrolidine ring and a heterocyclic coupler or a hydroxybenzamide [P]. Europe: EP 1428510, 2004, 6: 16.
[33] Qi J, Ojika M, Sakagami Y. Termitomycesphins A-D, Novel Neuritogenic Cerebrosides from the Edible Chinese Mushroom Termitomyces albuminosus. Tetrahedron 2000, 56(32): 5835-5841.
[1] Skehan P, Storeng R, Scudiero D, et al. New colorimetric cytotoxicity assay for anticancer drug screening. J. Natl. Cancer Inst. 1990, 82 (13): 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.
[5] Yun B S, Lee I K, Yoo I D, et al. Two p-terphenyls from mushroom Paxillus panuoides with free radical scavenging activity. J. Micobiol. Biotechnol. 2000, 10, 233-237.
1. Quilico A, Panizzi L. Chemical investigations of Aspergillus echinulatus. I. Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen. 1943, 76B: 348-358.
2. Quilico A, Cardani C. The diffusion of echinulin in molds of the group Aspergillus glaucus. Atti accad. nazl. Lincei, Rend. classesci. fis., mat. e nat. 1950, 9: 220-8.
3. Kitamura J, Kurimoto U, Yokoyama M. Metabolic products of Aspergillus chevalieri. Yakugaku Zasshi 1956, 76: 972-973.
4. Westley J W, Close V A, Nitecki D N, et al. Determination of steric purity and configuration of diketopiperazines by gas-liquid chromatography, thin-layer chromatography, and nuclear magnetic resonance spectrometry. Anal. Chem. 1968, 40(12): 1888-1890.
5. Barbetta M, Casnati G, Pochini A, et al. Neoechinuline: a new indole metabolite from Aspergillus amstelodami. Tetrahedron Lett. 1969, 51: 4457-4460.
6. Dossena A, Marchelli R, Pochini A. New metabolites of Aspergillus amstelodami related to the biogenesis of neoechinulin. J. Chem. Soc., Chem. Commun. 1974, 19: 771-772.
7. Dossena A, Marchelli R, Pochini A. Neoechinulin D, a new isoprenylated dehydrotryptophyl metabolite from Aspergillus amstelodami. Experientia. 1975, 31(11), 1249.
8. Marchelli R, Dossena A, Pochini A, et al. The structures of five new didehydropeptides related to neoechinulin, isolated from Aspergillus amstelodami. J. Chem. Soc., Perkin Trans. 1. 1977: 713–717.
9. Gatti G, Fuganti C. Carbon-13 NMR spectra of echinuline and related compounds. J. Chem. Res. Synop. 1979, 11: 366-367.
10. Nagasawa H, Isogai A, Ikeda K, et al. Isolation and structure elucidation of a new indole metabolite from Aspergillus ruber. Agr. Biol. Chem. 1975, 39(9): 1901-1902
11. Yagi R, Doi M. Isolation of an antioxidative substance produced by Aspergillus repens. Biosci. Biotech. Bioch. 1999, 63(5): 932-933.
12. Wang S, Li X, Teuscher F, et al. Chaetopyranin, a benzaldehyde derivative, and other related metabolites from Chaetomium globosum, an endophytic fungus derived from the marine red alga Polysiphonia urceolata. J. Nat. Prod. 2006, 69(11): 1622-1625.
13. Allen C M, Jr. Biosynthesis of echinulin. Isoprenylation of cyclo-L-alanyl-L-tryptophanyl. Biochemistry.1972, 11(11): 2154-2160.
14. Allen C M, Jr. Monoisoprenylated cyclo-L-alanyl-L-tryptophanyl. Biosynthetic precursor ofechinulin. J. Am. Chem. Soc. 1973, 95(7): 2386-2387.
15. Hamasaki T, Nagayama K, Hatsuda Y. Structure of a new metabolite from Aspergillus chevalieri. Agr. Biol. Chem. 1976, 40(1): 203-205
16. Nagasawa H, Isogai A, Suzuki A, et al. Structures of isoechinulins A, B and C, new indole metabolites from Aspergillus ruber. Tetrahedron Lett. 1976, 19: 1601-1604.
17. 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(8): 1759-1763.
18. Inoue S, Murata J, Takamatsu N, et al. Synthetic studies on echinulin and related natural products. V. Isolation, structure and synthesis of echinulin-neoechinulin type alkaloids isolated from Aspergillus amstelodami. Yakugaku Zasshi. 1977, 97(5): 576-581.
19. Gatti G, Cardillo R, Fuganti C. Molecular structure of cryptoechinuline G, an isoprenylated dehydrotryptophan metabolite isolated from Aspergillus ruber. Tetrahedron Lett. 1978, 29: 2605-2606.
20. Fujimoto H, Fujimaki T, Okuyama E, et al. Immunomodulatory constituents from an ascomycete, Microascus tardifaciens. Chem. Pharm. Bull. 1999, 47(10): 1426-1432.
21. Ravikanth V, Niranjan Reddy V L, Ramesh P, et al. An immunosuppressive tryptophan-derived alkaloid from Lepidagathis cristata. Phytochemistry, 2001, 58(8): 1263-1266.
22. Itabashi T, Matsuishi N, Hosoe T, et al. Two new dioxopiperazine derivatives, arestrictins A and B, isolated from Aspergillus restrictus and Aspergillus penicilloides. Chem. Pharm. Bull. 2006, 54(12): 1639-1641.
23. Li Y, Li X, Kang J S, et al. New radical scavenging and ultraviolet-A protecting prenylated dioxopiperazine alkaloid related to isoechinulin A from a marine isolate of the fungus Aspergillus. J. Antibiot. 2004, 57: 337–340.
24. Kimoto K, Aoki T, Shibata Y, et al. Structure-activity relationships of neoechinulin A analogues with cytoprotection against peroxynitrite-induced PC12 cell death. J. Antibiot. 2007, 60(10): 614-621.
25. Wang W, Lu Z, Tao H, et al. Isoechinulin-type Alkaloids, Variecolorin A-L, from Halotolerant Aspergillus variecolor. J. Nat. Prod. 2007, 70: 1558–1564.
26. Cardillo R, Fuganti C, Ghiringhelli D, et al. New minor metabolites as Aspergillus amstelodami. Chimica elIndustria 1975, 57(10): 678-679.
27. Gatti G, Cardillo R, Fuganti C, et al. Structure determination of two extractives fromAspergillus amstelodami by nuclear magnetic resonance spectroscopy. J. Chem. Soc., Chem. Commun. 1976, 12: 435-436.
28. Wang W, Zhu T, Tao H, et al. Variecolortide A-C, three Novel Oxa-spiro-cyclodipeptides from the Halotolerant Fungus strain Aspergillus variecolor B-17 Chemistry & Biodiversity. 2007, 4: 2913-2919.
29. Houghton E, Saxton J E. Echinulin series. II. Synthesis of (+-)-alanyltryptophan anhydride and L-alanyl-2(1,1-dimethylallyl)tryptophan anhydride. J. Chem. Soc. Org. 1969, 6: 1003-1012.
30. Takamatsu N, Inoue S, Kishi Y. Synthetic study on echinulin and related compounds. II. Stereoselective total synthesis of optically active echinulin. Tetrahedron Lett. 1971, 48: 4665-4668.
31. Plate R, Nivard Rutger J F, Ottenheijm H C J. Conversion of N-hydroxytryptophans into dehydrotryptophan. An approach to the neoechinulin series. J. Chem. Soc., Perkin Trans. 1, 1987, 11: 2473-2480.
32. Oikawa Y, Yoshioka T, Yonemitsu O. Synthesis of oxidized diketopiperazine alkaloids by the selective oxidation of C-3 side chains of indoles. Tennen Yuki Kagobutsu Toronkai Koen Yoshishu, 1978: 22-27.
33. Nakatsuka S, Miyazaki H, Goto T. Synthetic studies on natural products containing oxidized diketopiperazine. I. Total synthesis of neoechinulin A, an indole alkaloid containing oxidized diketopiperazine. Tetrahedron Lett, 1980, 21(29): 2817-2820.
34. Aoki T, Kamisuki S, Kimoto M, et al. Total synthesis of (-)-neoechinulin A. Synlett, 2006, 5: 677-680.
35. Birch A J, Blance G E, David S, et al. Studies in relation to biosynthesis. XXIV. Some remarks on the structure of echinuline. J. Chem. Soc., 1961: 128-31.
36. Marchelli R, Dossena A, Casnati G. Biosynthesis of neoechinulin by Aspergillus amstelodami from cyclo-L-alanyl-U-14C-L-tryptophyl-5,7-3H2. J. Chem. Soc., Chem. Commun., 1975, 19: 779-780.
2. Khmel I A. Regulation of expression of bacterial genes in the absence of active cell growth. Russ. J. Genet. 2005, 41: 968-984.
3. Schlictman D, Kubo M, Shankar S, et al. Regulation of nucleoside diphosphate kinase and secretable virulence factors in Pseudomonas aeruginosa: roles of algR2 and algH. J. Bacteriol. 1995, 177: 2469-2474.
4. Tamburini E, Mastromei G. Do bacterial cryptic genes really exist? Res. Microbiol. 2000, 151: 179-182.
5. Koch A L. Genetic response of microbes to extreme challenges. J. Theor. Biol. 1993, 160: 1-21.
6. Mejanelle L, Lopez J F, Gunde-Cimerman N, Grimalt J O. Ergosterol biosynthesis in novel melanized fungi from hypersaline environments. J. Lipid Res. 2001, 42: 352-358.
7. Werner E G M, Heinz C S, Matthias W, et al. Isabel M. M. Traditional and Modern Biomedical Prospecting: Part II - the Benefits. eCAM, 2004, 1(2): 133-144
8. Werner E G M, Renato B, Heinz C S, et al. Traditional and Modern Biomedical Prospecting: Part I - the History, Sustainable Exploitation of Biodiversity (Sponges and Invertebrates) in the Adriatic Sea in Rovinj (Croatia). eCAM, 2004, 1(1): 71-82.
9.肖建球。海洋微生物代谢物抗肿瘤活性的研究进展。中医药导报,2005, 11(7): 95-96.
10. Larsen T O, Smedsgaard J, Nielsen K F, et al. Phenotypic taxonomy and metabolite profiling in microbial drug discovery. Nat Prod Rep, 2005, 22, 672-695
[1] Solis P N, Wright C W, Anderson M M, et al. A microwell cytotoxicity assay using Artemia salina (brine shrimp). Planta Med., 1993, 59(3): 250-252.
[2] Meyer B N, Ferrigni N R, Putnam J E, et al. Brine Shrimp: A convenient general bioassay for active plant constituents. Planta Med., 1982, 45(1): 31-34.
[3]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(6): 804-809.
[4]杰利·L·麦克劳林,顾哲明.两种建议的抗肿瘤活性初筛方法.中国中药杂志, 1997, 22(10): 617-619.
[5] Yun B S, Lee I K, Yoo I D, et al. Two p-terphenyls from mushroom Paxillus panuoides with free radical scavenging activity. J. Micobiol. Biotechnol., 2000, 10: 233-237.
[6] Cui C B, Zhao Q C, Cai B, et al. Two new and four known polyphenolics obtained as new cell-cycle inhibitors from Rubus aleaefolius Poir. J. Asian Nat. Prod. Res., 2002, 4 (4): 243-252.
[7]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筛选.青岛海洋大学学报. 2002, 32(123), 123-126.
[1] Marchelli R, Dossena A, Pochini A, et al. The structures of five new didehydropeptides related to neoechinulin, isolated from Aspergillus amstelodami. J. Chem. Soc. PerkinⅠ, 1977:713-717
[2] Wakulinski W, Kachlicki P, Sobiczewski P, et al. Catenarin production by isolates of Pyrenophora tritici-repentis (Died.) Drechsler and its antimicrobial activity. J. Phytopathol. 2003, 151: 74-79.
[3] Li Y, Li X, Kang J S, et al. New radical scavenging and ultraviolet-A protecting prenylated dioxopiperazine alkaloid related to isoechinulin A from a marine isolate of the fungus Aspergillus. J. Antibiot. 2004, 57: 337–340.
[4] Barbetta M, Casnati G., Pochini A, et al. Neoechinuline: a new indole metabolite from Aspergillus amstelodami. Tetrahedron Lett. 1969, 51: 4457-4460.
[5] Gatti G., Fuganti C. Carbon-13 NMR spectra of echinuline and related compounds. J. Chem. Res. Synop. 1979, 11: 366-367.
[6] Nagasawa H, Isogai A, Suzuki A, et al. Structures of isoechinulins A, B and C, new indole metabolites from Aspergillus ruber. Tetrahedron Lett. 1976, 19: 1601-1604.
[7] 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(8): 1759-1763.
[8]范国涛。海洋来源真菌KLEB-07、H2-02和WZ4-F22次级代谢产物抗肿瘤活性成分研究。中国海洋大学2005届硕士论文。
[9] Quilico A, Panizzi L. Chemical investigations of Aspergillus echinulatus. I. Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen. 1943, 76B: 348-358.
[10] Quilico A, Cardani C. The diffusion of echinulin in molds of the group Aspergillus glaucus. Atti accad. nazl. Lincei, Rend. classesci. fis., mat. e nat. 1950, 9: 220-228.
[11] Kitamura J, Kurimoto U, Yokoyama M. Metabolic products of Aspergillus chevalieri. Yakugaku Zasshi 1956, 76: 972-973.
[12] Fujimoto H, Fujimaki T, Okuyama E, et al. Immunomodulatory constituents from anascomycete, Microascus tardifaciens. Chem. Pharm. Bull. 1999, 47(10): 1426-1432.
[13] Yagi R, Doi M. Isolation of an antioxidative substance produced by Aspergillus repens. Biosci. Biotechnol. Biochem., 1999, 63: 932-933.
[14] Dossena A, Marchelli R, Pochini A. New metabolites of Aspergillus amstelodami related to the biogenesis of neoechinulin. J. Chem. Soc. Chem. Comm., 1974: 771-772.
[15] Houghton E, Saxton J E. Echinuluin series.Ⅱ. Synthesis of (+)-alanyl- tryptophan anhydride and L-alanyl-2-(1,1-dimethylallyl)tryptophan anhydride. J. Chem. Soc. [section] C: Organic, 1969(6): 1003-1012
[16] Stipanovic R D, Schroeder H. Preechinulin, a metabolite of Aspergillus chevalieri. Transactions of the British Mycological Society, 1976, 66: 178-179
[17] Takashi H, Kouzou N, Yuichi H. A new metabolite, L-alanyl-L-tryptophan anhydride from Aspergillus chevalieri. Agr. Boil. Chem., 1976, 40 (12): 2487
[18] Nakashima Ruka, Slater, G P. Configuration of echinulin. Tetrahedron Letters, 1967, 45: 4433-4436.
[19] Stipanovic R D, Schroeder H W, Hein H J. Identification of D-valyl-L-tryptophan anhydride from Aspergillus chevalieri. Lloydia, 1976, 39(2-3): 158-159.
[20] Nakashima R, Slater G P. Configuration of echinulin. II. Optical rotatory dispersion of echinulin, hydroechinulin, and the stereoisomeric 3-methyl-6-(incolyl-3-methyl)piperazine- 2,5-diones. Can. J. Chem., 1969, 47 (11): 2069-2074.
[21] Birch A J, Blance G E, David S, et al. J. Chem. Soc., 1961: 3128-3131
[22] Talapatra S K, Mandal S K, Bhaumik A, et al. Echinulin, a novel cyclic dipeptide carrying a triprenylated indole moiety from an Anacardiaceae, a Cucurbitaceae and two Orchidaceae plants: detailed high resolution 2D-NMR and mass spectral studies. Journal of the Indian Chemical Society, 2001, 78(10-12): 773-777
[23] Inoue S, Murata J, Takamatsu N, et al. Synthetic studies on echinulin and related natural products. V. Isolation, structure and synthesis of echinulin-neoechinulin type alkaloids isolated from Aspergillus amstelodami. Yakugaku Zasshi. 1977, 97(5): 576-581.
[24] Gatti G, Cardillo R, Fuganti C. Molecular structure of cryptoechinuline G, an isoprenylated dehydrotryptophan metabolite isolated from Aspergillus ruber. Tetrahedron Lett. 1978, 29: 2605-2606.
[25] Segaw A, Miyaichi Y, Tomimori T, et al. Studieson nepalese crude drugs XXV. Phenolic constituents of theleaves of Didymocarpus leucocalyx C. B. Clarke (Gesnerriaceae). Chem Pharm Bull. 1999,47: 1404–1411
[26]许颂,梁华清.刺人参的蒽醌成分研究.中草药, 1998, 29(4): 222-223.
[27] Alemayehu G, Abegaz B, Snatzke G, et al. Bianthraquinone alkaloid from Cassia floribunda. Phytochemistry, 1988, 27 (10): 3255-3258
[28] Coskun M, Tanker N, Sakushima A, et al. An anthraquinone glycoside from Rhamnus pallasii. Phytochemistry, 1984, 23 (7): 1485-1487.
[29] Kalidhar S B. Structural elucidation in anthraquinones using 1H NMR glycosylation and alkylation shifts. Phytochemstry, 1989, 28 (12): 3459-3463
[30]李建北,林茂.何首乌化学成分的研究.中草药, 1993, 24 (3): 115-118
[31] Anke H, Kolthoum I, Laatsch H. Metabolic products of microorganisms. 192. The anthraquinones of the Aspergillus glaucus group. II. Biological activity. Arch Microbiol, 1980, 126: 231–236
[32] Eder C, Kogler H, Toti L. Preparation of eurotinone, a KDR kinase inhibitor from Eurotium echinulatum (DSM 13872). 2003, WO 2003002549.
[33] Hamasaki T, Kimura Y, Hatsuda Y, et al. Structure of a new metabolite, dihydroauroglaucin, produced by Aspergillus chevalieri. Agric. Biol. Chem. 1981, 45(1): 313-314.
[34] Hamasaki T, Fukunaga M, Kimura Y, et al. Isolation and structures of two new metabolites from Aspergillus ruber. Agric. Biol. Chem. 1980, 44(7): 1685-1687.
[35] Itokawa H, Akita Y, Yamazaki M. Indole derivatives isolated from the oil cakes of Camellia seeds. Relation to the components of the fungus infecting the oil cakes. Yakugaku Zasshi 1973, 93(9): 1251-1252.
[36] Nitta K, Fujita N, Yoshimura T, et al. Metabolic products of Aspergillus terreus. IX. Biosynthesis of butyrolactone derivatives isolated from strains IFO 8835 and 4100. Chem. Pharm. Bull. 1983, 31(5): 1528-1533.
[37] Niu X, Dahse H, Menzel K, et al. Butyrolactone I derivatives from Aspergillus terreus carrying an unusual sulfate moiety. J. Nat. Prod. (release online).
[38] Allen C M Jr. Biosynthesis of echinulin. Isoprenylation of cyclo-L-alanyl-L-tryptophanyl. Biochemistry, 1972, 11 (11): 2154-2160。
[39] Allen C M Jr. Monoisoprenylated cyclo-L-alanyl-L-tryptophanyl. A biosynthetic precursor of echinulin. J. Am. Chem. Soc., 1973, 95 (7): 2386-2387。
[40] Li Y, Li X, Kim S K, et al. Golmaenone, a new diketopiperazine alkaloid from the marine-derived fungus Aspergillus sp.. Chem. Pharm. Bull., 2004, 52 (3): 375-376
[41] Ravikanth V, Niranjan Reddy V L, Ramesh P, et al. An immunosuppressive tryptophan-derived alkaloid from Lepidagathis cristata. Phytochemistry, 2001, 58: 1263-1266
[42] Yukihiro I, Kyozo M, Takashi H. Metabolites of Eurotium species, their antioxidative properties and synergism with tocopherol. Journal of Food Science, 1985, 50 (6): 1742-1744
[43] Kiyoshi K, Kazuo H, Teruhiko N, et al. Inhibition of mitochondrial electron transport system by flavoglaucin from Eurotium chevalieri. II. The interaction with complex III. Mycotoxins, 1986, 24: 13-18.
[44] Kiyoshi K, Hideki M, Jiro K. The uncoupling effect of flavoglaucin, a quinol pigment from Aspergillus chevalieri (Mangin), on mitochondrial respiration. Toxicology Letters, 1983, 19 (3): 321-325
[1] Zhan Z J, Yue J M. New glycophingolipids from the fungus Catathelasma ventricosa. J. Nat. Prod., 2003, 66: 1013-1016
[2] Sitrin R D, Chan G, Dingerdissen J, et al. Isolation and structure determination of Pachybasium cerebrosides which potentiate the antifungal activity of aculeacin. J. Antibiotic., 1988, 41 (4): 469-480
[3] Keusgen M, Yu C M, Curtis J M, et al. A cerebroside from the marine fungus Microsphaeropsis olivacea (bonord) H?hn. Biochemical Systematics and Ecology, 1996, 24 (5): 465-468。
[4] Walker T E, London R E, Whaley T W, et al. Carbon-13 nuclear magnetic resonance spectroscopy of [1-13C] enriched monosaccharides. Signal assignments and orientational dependence of geminal and vicinal carbon-carbon and carbon-hydrogen spin-spin coupling constants. J. Am. Chem. Soc., 1976, 98 (19): 5807-5813
[5] Kang S S, Kim J S, Xu Y N, et al. Isolation of a new cerebroside from the root bark of Aralia elata. J. Nat.Prod., 1999, 62: 1059-1060
[6] Qi J H, Ojika M, Sakagami Y. Termitomycesphins A-D, novel neuritogenic cerebrosides from the edible Chinese mushroom Termitomyces albuminosus. Tetrahedron, 2000, 56: 5835-5841
[7] Jin W Z, Rinehart K L, Jares-Erijman E A. Ophidiacerebrosides: cytotoxic glycosphingolipids containing a novel sphingosine from a sea star. J. Org. Chem., 1994, 59: 144-147.
[8] Kim S Y, Choi Y H, Huh H, et al. New antihepatotoxic cerebroside from Lycium chinense fruits. J. Nat. Prod., 1997, 60: 274-276。
[9] Sugimura H, Yoshida K. Diastereoselective reduction of chiralβ,γ-unsaturated a-Oxo esters. Asymmetric synthesis of thefatty acid moiety of symbioramide. J. Org. Chem., 1993, 58: 4484-4486
[10] Takanami T, Tokoro H, Kato D, et al. Chemo-enzymatic short-step total synthesis of symbioramide. Tetrahedron Lett., 2005, 46: 3291–3295
[11] Shu R G, Wang F W, Yang Y M, et al. Antibacterial and Xanthine Oxidase InhibitoryCerebrosides from Fusarium sp. IFB-121, an Endophytic Fungus in Quercus variabilis Lipids, 2004, 39 (7): 667-673.
[12] Hora J, Labler L, Kasal A, et al. Steroids. CIII. Molting deficiencies produced by some sterol derivatives in an insect (Pyrrhocoris apterus). Steroids, 1966, 8(6): 887-914.
[13] Valisolalao J, Luu B, Ourisson G. Chemical and biochemical study of Chinese drugs. Part VIII. Cytotoxic steroids from Polyporus versicolor. Tetrahedron, 1983, 39(17): 2779-2785.
[14] Yaoita Y, Endo M, Tani Y, et al. Sterol constituents from seven mushrooms. Chem. Pharm. Bull. 1999, 47(6): 847-851.
[15] Aiello A, Ciminiello P, Fattorusso E, et al. 3β,5α-Dihydroxy-6β-methoxy- cholest-7-enes from the marine sponge Spongia agaricina. J. Nat. Prod., 1988, 51 (5): 999-1002
[16] Kawagishi H, Katsumi R, Sazawa T, et al. Cytotoxic steroids from the mushroom Agaricus blazei. Phytochemistry, 1988, 27 (9): 2777-2779
[17] Fujimoto Y, Yamada T, Ikekawa N. Pyridine-induced deshielding of 4-methylene protons for the determination of C-6 stereochemistry of sterols having a 5α,6-diol moiety. Revision of the stereochemistry of marine sterol isolated from a sponge, Dysidea sp. Chem. Pharm. Bull., 1985, 33 (8): 3129-3133
[18]高锦明,董泽军,刘吉开.蓝黄红姑的化学成分.云南植物研究,2000,22(1): 85-89
[19] Takaishi Y, Uda M, Ohashi T, et al. Glycosides of ergosterol derivatives from Hericum erinacens. Phytochemstry, 1991, 30 (12): 4117-4120
[20] De Riccardis F, Spinella A, Izzo I, et al. Synthesis of (17R)-17-methylincisterol, a highly degraded marine steroid. Tetrahedron Lett. 1995, 36(24): 4303-4306.
[21] Mansoor T A, Hong J, Lee C O, et al. Cytotoxic sterol derivatives from a marine sponge Homaxinella sp. J. Nat. Prod. 2005, 68(3): 331-336.
[22] Rahman R, Safe S, Taylor A. Separation of polythiadioxopiperazine antibiotics by thin-layer chromatography. J. Chromatography, 1970, 53(3): 592-594
[23] Rastetter W H, Chancellor T, Richard T J. Biogenesis of epidithiadioxopiperazines. Nucleophilic additions to benzene oxide and sym-oxepin oxide. J. Org. Chem. 1982, 47(8): 1509-1512.
[24] Okuno T, Natsume I, Sawai K, et al. Structure of antifungal and phytotoxic pigments produced by Alternaria species. Tetrahedron Lett. 1983, 24(50): 5653-5656.
[25] Arnone A, Assante G, Caronna T, et al. Comparative evaluation of photodynamic efficiency of some natural quinonoid fungal toxins. Phytochemistry 1988, 27(6): 1669-1674.
[26] Stinson E E, Osman S F, Pfeffer P E. Structure of Altertoxin I, a mycotoxin from Alternaria. J. Org. Chem. 1982, 47(21): 4110-4113
[27]李想,姚燕华,郑毅男,等。红树林植物海漆的化学成分(Ⅰ).中国天然药物, 2006, 4(3): 188-191。
[28]胡海峰,朱宝泉,龚炳.微生物来源的胆固醇生物合成醇抑制剂研究:抗生素SIPI-8926-111的研究.中国医药工业杂志, 1995, 26 (11), 484-486.
[29]熊江,周俊,戴好富.多蕊商陆的化学成分.云南植物研究, 2002, 24: 401-403
[30] Sebedio J L, Bonpunt A, Grandgirard A, et al. Deep fat frying of frozen prefried french fries: influence of the amount of linolenic acid in the frying medium. J. Agr. Food Chem 1990, 38(9): 1862-1867.
[31]丁智慧,丁靖垲,易元芬.细梗香草的挥发油成分.云南植物研究. 1989, 11(2): 209-214
[32] Cotteret J, Lagrange A. Hair dyeing compositions comprising a tertiary p-phenylenediamine with a pyrrolidine ring and a heterocyclic coupler or a hydroxybenzamide [P]. Europe: EP 1428510, 2004, 6: 16.
[33] Qi J, Ojika M, Sakagami Y. Termitomycesphins A-D, Novel Neuritogenic Cerebrosides from the Edible Chinese Mushroom Termitomyces albuminosus. Tetrahedron 2000, 56(32): 5835-5841.
[1] Skehan P, Storeng R, Scudiero D, et al. New colorimetric cytotoxicity assay for anticancer drug screening. J. Natl. Cancer Inst. 1990, 82 (13): 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.
[5] Yun B S, Lee I K, Yoo I D, et al. Two p-terphenyls from mushroom Paxillus panuoides with free radical scavenging activity. J. Micobiol. Biotechnol. 2000, 10, 233-237.
1. Quilico A, Panizzi L. Chemical investigations of Aspergillus echinulatus. I. Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen. 1943, 76B: 348-358.
2. Quilico A, Cardani C. The diffusion of echinulin in molds of the group Aspergillus glaucus. Atti accad. nazl. Lincei, Rend. classesci. fis., mat. e nat. 1950, 9: 220-8.
3. Kitamura J, Kurimoto U, Yokoyama M. Metabolic products of Aspergillus chevalieri. Yakugaku Zasshi 1956, 76: 972-973.
4. Westley J W, Close V A, Nitecki D N, et al. Determination of steric purity and configuration of diketopiperazines by gas-liquid chromatography, thin-layer chromatography, and nuclear magnetic resonance spectrometry. Anal. Chem. 1968, 40(12): 1888-1890.
5. Barbetta M, Casnati G, Pochini A, et al. Neoechinuline: a new indole metabolite from Aspergillus amstelodami. Tetrahedron Lett. 1969, 51: 4457-4460.
6. Dossena A, Marchelli R, Pochini A. New metabolites of Aspergillus amstelodami related to the biogenesis of neoechinulin. J. Chem. Soc., Chem. Commun. 1974, 19: 771-772.
7. Dossena A, Marchelli R, Pochini A. Neoechinulin D, a new isoprenylated dehydrotryptophyl metabolite from Aspergillus amstelodami. Experientia. 1975, 31(11), 1249.
8. Marchelli R, Dossena A, Pochini A, et al. The structures of five new didehydropeptides related to neoechinulin, isolated from Aspergillus amstelodami. J. Chem. Soc., Perkin Trans. 1. 1977: 713–717.
9. Gatti G, Fuganti C. Carbon-13 NMR spectra of echinuline and related compounds. J. Chem. Res. Synop. 1979, 11: 366-367.
10. Nagasawa H, Isogai A, Ikeda K, et al. Isolation and structure elucidation of a new indole metabolite from Aspergillus ruber. Agr. Biol. Chem. 1975, 39(9): 1901-1902
11. Yagi R, Doi M. Isolation of an antioxidative substance produced by Aspergillus repens. Biosci. Biotech. Bioch. 1999, 63(5): 932-933.
12. Wang S, Li X, Teuscher F, et al. Chaetopyranin, a benzaldehyde derivative, and other related metabolites from Chaetomium globosum, an endophytic fungus derived from the marine red alga Polysiphonia urceolata. J. Nat. Prod. 2006, 69(11): 1622-1625.
13. Allen C M, Jr. Biosynthesis of echinulin. Isoprenylation of cyclo-L-alanyl-L-tryptophanyl. Biochemistry.1972, 11(11): 2154-2160.
14. Allen C M, Jr. Monoisoprenylated cyclo-L-alanyl-L-tryptophanyl. Biosynthetic precursor ofechinulin. J. Am. Chem. Soc. 1973, 95(7): 2386-2387.
15. Hamasaki T, Nagayama K, Hatsuda Y. Structure of a new metabolite from Aspergillus chevalieri. Agr. Biol. Chem. 1976, 40(1): 203-205
16. Nagasawa H, Isogai A, Suzuki A, et al. Structures of isoechinulins A, B and C, new indole metabolites from Aspergillus ruber. Tetrahedron Lett. 1976, 19: 1601-1604.
17. 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(8): 1759-1763.
18. Inoue S, Murata J, Takamatsu N, et al. Synthetic studies on echinulin and related natural products. V. Isolation, structure and synthesis of echinulin-neoechinulin type alkaloids isolated from Aspergillus amstelodami. Yakugaku Zasshi. 1977, 97(5): 576-581.
19. Gatti G, Cardillo R, Fuganti C. Molecular structure of cryptoechinuline G, an isoprenylated dehydrotryptophan metabolite isolated from Aspergillus ruber. Tetrahedron Lett. 1978, 29: 2605-2606.
20. Fujimoto H, Fujimaki T, Okuyama E, et al. Immunomodulatory constituents from an ascomycete, Microascus tardifaciens. Chem. Pharm. Bull. 1999, 47(10): 1426-1432.
21. Ravikanth V, Niranjan Reddy V L, Ramesh P, et al. An immunosuppressive tryptophan-derived alkaloid from Lepidagathis cristata. Phytochemistry, 2001, 58(8): 1263-1266.
22. Itabashi T, Matsuishi N, Hosoe T, et al. Two new dioxopiperazine derivatives, arestrictins A and B, isolated from Aspergillus restrictus and Aspergillus penicilloides. Chem. Pharm. Bull. 2006, 54(12): 1639-1641.
23. Li Y, Li X, Kang J S, et al. New radical scavenging and ultraviolet-A protecting prenylated dioxopiperazine alkaloid related to isoechinulin A from a marine isolate of the fungus Aspergillus. J. Antibiot. 2004, 57: 337–340.
24. Kimoto K, Aoki T, Shibata Y, et al. Structure-activity relationships of neoechinulin A analogues with cytoprotection against peroxynitrite-induced PC12 cell death. J. Antibiot. 2007, 60(10): 614-621.
25. Wang W, Lu Z, Tao H, et al. Isoechinulin-type Alkaloids, Variecolorin A-L, from Halotolerant Aspergillus variecolor. J. Nat. Prod. 2007, 70: 1558–1564.
26. Cardillo R, Fuganti C, Ghiringhelli D, et al. New minor metabolites as Aspergillus amstelodami. Chimica elIndustria 1975, 57(10): 678-679.
27. Gatti G, Cardillo R, Fuganti C, et al. Structure determination of two extractives fromAspergillus amstelodami by nuclear magnetic resonance spectroscopy. J. Chem. Soc., Chem. Commun. 1976, 12: 435-436.
28. Wang W, Zhu T, Tao H, et al. Variecolortide A-C, three Novel Oxa-spiro-cyclodipeptides from the Halotolerant Fungus strain Aspergillus variecolor B-17 Chemistry & Biodiversity. 2007, 4: 2913-2919.
29. Houghton E, Saxton J E. Echinulin series. II. Synthesis of (+-)-alanyltryptophan anhydride and L-alanyl-2(1,1-dimethylallyl)tryptophan anhydride. J. Chem. Soc. Org. 1969, 6: 1003-1012.
30. Takamatsu N, Inoue S, Kishi Y. Synthetic study on echinulin and related compounds. II. Stereoselective total synthesis of optically active echinulin. Tetrahedron Lett. 1971, 48: 4665-4668.
31. Plate R, Nivard Rutger J F, Ottenheijm H C J. Conversion of N-hydroxytryptophans into dehydrotryptophan. An approach to the neoechinulin series. J. Chem. Soc., Perkin Trans. 1, 1987, 11: 2473-2480.
32. Oikawa Y, Yoshioka T, Yonemitsu O. Synthesis of oxidized diketopiperazine alkaloids by the selective oxidation of C-3 side chains of indoles. Tennen Yuki Kagobutsu Toronkai Koen Yoshishu, 1978: 22-27.
33. Nakatsuka S, Miyazaki H, Goto T. Synthetic studies on natural products containing oxidized diketopiperazine. I. Total synthesis of neoechinulin A, an indole alkaloid containing oxidized diketopiperazine. Tetrahedron Lett, 1980, 21(29): 2817-2820.
34. Aoki T, Kamisuki S, Kimoto M, et al. Total synthesis of (-)-neoechinulin A. Synlett, 2006, 5: 677-680.
35. Birch A J, Blance G E, David S, et al. Studies in relation to biosynthesis. XXIV. Some remarks on the structure of echinuline. J. Chem. Soc., 1961: 128-31.
36. Marchelli R, Dossena A, Casnati G. Biosynthesis of neoechinulin by Aspergillus amstelodami from cyclo-L-alanyl-U-14C-L-tryptophyl-5,7-3H2. J. Chem. Soc., Chem. Commun., 1975, 19: 779-780.