两株海洋放线菌细胞毒活性成分研究
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摘要
目的对海洋放线菌Micromonospora sp. (No. M2DG17)以及Streptomyces sp. (No.0616121)中的细胞毒活性成分进行研究。方法采用活性追踪分离的方法,综合利用硅胶开放柱色谱、ODS中低压柱色谱、Sephadex LH-20凝胶柱色谱以及高效液相色谱等分离手段进行化合物的分离、纯化；利用理化性质和波谱学分析等方法对单体化合物进行结构鉴定,并对其进行活性评价。结果从海洋放线菌Micromonospora sp. (No. M2DG17)发酵物中分离得到了12个化合物,其结构分别为3-羟甲基-β-卡巴林(化合物1)、3-甲基-β-卡巴林(化合物2)、β-卡巴林(化合物3)、麦芽酚(化合物4)、环(L-脯-L-苯丙)二肽(化合物5)、环(L-脯-L-缬)二肽(化合物6)、环(L-脯-L-亮)二肽(化合物7)、环(L-脯-L-异亮)二肽(化合物8)、邻苯二甲酸二(2-乙基-己基)酯(化合物9)、邻苯二甲酸异丁酯(化合物10)、苯乙酸(化合物11)、大豆素(化合物12)。其中化合物1-5、7-10,为首次从该属放线菌中分离得到,化合物2显示出弱的HCT 116细胞生长抑制活性(IC50为65.0μM)；从菌株Streptomyces sp. (No.0616121)发酵物中分离得到9个化合物,其中4个化合物与化合物5-8结构相同,另外5个化合物的结构分别为邻苯二甲酸正丁酯(化合物13)、环(D-脯-L-缬)二肽(化合物14)、环(L-脯-L-甲硫)二肽(化合物15)、环(D-脯-L-异亮)二肽(化合物16)、环(丙-缬)二肽(化合物17)。其中化合物15为首次从该属放线菌中分离得到。
Objective To study the bioactive secondary metabolites from two strains of marine-derived Actinomycetes Micromonospora sp. (M2DG17) and Streptomyces sp. (0616121). Methods By bioassay-guided fractionation, various chromatographic and spectroscopic methods were applied for the isolation and structural identification of pure compounds from the broth of Micromonospora sp. (M2DG17) and Streptomyces sp. (0616121). Results Twelve compounds were obtained from the broth of Micromonospora sp. (M2DG17) and their structures were identified as 3-hydroxymethyl-β-carboline (compound 1),3-methyl-β-carboline (compound 2), P-carboline (compound 3),3-Hydroxy-2-methyl-4-pyrone (compound 4), Cyclo-(L-Pro-L-Phe) (compound 5), Cyclo-(L-Pro-L-Leu) (compound 6), Cyclo-(L-Pro-L-Val) (compound 7), and Cyclo-(L-Pro-L-Ile) (compound 8), Phthalate(2-ethyl)hexyl (compound 9), Isobutyl phthalate (compound 10), Phenylacetic Acid (compound 11), and Daidzein (compound 12), respectively. Compound 1-5,7-10 were isolated from the genus of Micromonospora sp. (M2DG17) for the first time, and compound 2 showed weak inhibitory effect on HCT 116 cell lines with IC50 values of 65.0μM. Nine compounds were obtained from the broth of Streptomyces sp. (0616121) respectively., and four compounds were identical with compounds 5-10. The other five ones were identified as Dibutyi phthalate(compound 13), Cyclo-(D-Pro-L-Val) (compound 14), Cyclo- (L-Pro-L-Met) (compound 15), Cyclo- (D-Pro-L-Ile) (compound 16), Cyclo (Ala-Leu) (compound 17). Compound 15 were isolated from the genus of Streptomyces sp. (0616121) for the first time.
Objective To study the bioactive secondary metabolites from two strains of marine-derived Actinomycetes Micromonospora sp. (M2DG17) and Streptomyces sp. (0616121). Methods By bioassay-guided fractionation, various chromatographic and spectroscopic methods were applied for the isolation and structural identification of pure compounds from the broth of Micromonospora sp. (M2DG17) and Streptomyces sp. (0616121). Results Twelve compounds were obtained from the broth of Micromonospora sp. (M2DG17) and their structures were identified as 3-hydroxymethyl-β-carboline (compound 1),3-methyl-β-carboline (compound 2), P-carboline (compound 3),3-Hydroxy-2-methyl-4-pyrone (compound 4), Cyclo-(L-Pro-L-Phe) (compound 5), Cyclo-(L-Pro-L-Leu) (compound 6), Cyclo-(L-Pro-L-Val) (compound 7), and Cyclo-(L-Pro-L-Ile) (compound 8), Phthalate(2-ethyl)hexyl (compound 9), Isobutyl phthalate (compound 10), Phenylacetic Acid (compound 11), and Daidzein (compound 12), respectively. Compound 1-5,7-10 were isolated from the genus of Micromonospora sp. (M2DG17) for the first time, and compound 2 showed weak inhibitory effect on HCT 116 cell lines with IC50 values of 65.0μM. Nine compounds were obtained from the broth of Streptomyces sp. (0616121) respectively., and four compounds were identical with compounds 5-10. The other five ones were identified as Dibutyi phthalate(compound 13), Cyclo-(D-Pro-L-Val) (compound 14), Cyclo- (L-Pro-L-Met) (compound 15), Cyclo- (D-Pro-L-Ile) (compound 16), Cyclo (Ala-Leu) (compound 17). Compound 15 were isolated from the genus of Streptomyces sp. (0616121) for the first time.
引文
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[2]Krohn K, Dictionary of Marine Natural Products edited by John W. Blunt and Murray H.G. Munro. [J]. Angew Chem, Int Ed,2008,47(27):4956.
[3]Blunt J W, Copp B R, Hu W P, et al. Marine natural products [J]. Nat Prod Rep, 2009,26(2):170.
[4]Blunt J W, Copp B R, Hu W P, et al. Marine natural products [J]. Nat Prod Rep, 2008,25(1):35.
[5]Burkholder P R, Pfister R M, Leitz F H. Production of a pyrrole antibiotic by a marine bacterium [J]. Appl Microbiol,1966,14(4):649.
[6]Rinehart K L, Holt T G, Fregeau N L. Ecteinascidins 729,743,745,759A,759B, and 770:potent antitumor agents from the Caribbean tunicate Ecteinascidia turbinata [J].J Org Chem,1990,55(15):4512.
[7]Robert W, Schumacher, Stephanie C. Isolation and structure determination of an antimicrobial ester from a marine sediment-derived bacterium [J]. JNat Prod,2003, 66(9):1291.
[8]Mckee T C, Cardellina J H, et al. HIV-inhibitory natural products.11. Comparative studies of sulfated sterols from marine invertebrates [J]. J. Med. Chem., 1994,37(6):793.
[9]Fuhrman F A, Fuhrman G J, et.al. Doridosine:a new hypotensive N-methylpurine riboside from the nudibranch Anisodoris nobilis.Science,1980,207(4427):193.
[10]Ferlay J, Shin H R, Bray F, et al. Estimates of worldwide burden of cancer in 2008:GLOBOCAN 2008 [J]. Int J Cancer,2010,127(12):2893.
[11]代敏,李霓等.全球肿瘤预防控制概况.中国肿瘤,2011,20(1)：21.
[12]Jordan M A, Kamath K, Manna T, et al. The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth [J]. Mol Cancer Ther,2005,4(7):1086.
[13]Li C, Komaki R, Herbst R S, et al. A phase III study of E2941 with induction chemotherapy (IC) and concom itant chemora2 diotherapy (CRT) for stage III non2small cell Lung cancer(NSCLC) (NCI T9920046, RTOG 02270,MDA 992303): An inter im report of toxicity and response. J Clin Oncol,2005,23:S7144.
[14]Clamp A R, Blackhall F H, Vasey P, et al. A phase Ⅱ trial of bryostatin-1 administered by weekly 24-hour infusion in recurrent epithelial ovarian carcinoma [J]. Br J Cancer,2003,89(7):1152.
[15]McDermott D F, Hersh E, Weber J, et al. ILX651 administered daily for five days every 3 weeks (qdx5dq3w) in patients (pts) with inoperable locally advanced or metastatic melanoma:Phase Ⅱ experience[J]. J Clin Oncol,2005,23:7556.
[16]Kerbrat P, Dieras V, Pavlidis N, et al. Phase Ⅱ study of LU 103793 (dolastatin analogue) in patients with metastatic breast cancer [J]. Eur J Cancer,2003,39(3): 317.
[17]Patel S, Keohan M L, Saif M W, et al. Phase Ⅱ study of intravenous TZT-1027 in patients with advanced or metastatic soft-tissue sarcomas with prior exposure to anthracycline-based chemotherapy [J]. Cancer,2006,107(12):2881.
[18]Moneo V, Serelde B G, Leal J F, et al. Levels of p27(kip1) determine Aplidin sensitivity [J]. Mol Cancer Ther,2007,6(4):1310.
[19]Rademaker-Lakhai J M, Horenblas S, Meinhardt W, et al. Phase Ⅰ clinical and pharmacokinetic study of kahalalide F in patients with advanced androgen refractory prostate cancer [J]. Clin Cancer Res,2005,11(5):1854.
[20]Ratain M J, Undevia S, Janisch L, et al. Phase 1 and pharmacological study of HTI-286, a novel antimicrotubule agent:Correlation of neutropenia with time above a threshold serum concentration [C]. Proc Am Soc Clin Oncol,2003,22.
[21]Hoffman M A, Blessing J A, Lentz S S. A phase Ⅱ trial of dolastatin-10 in recurrent platinum-sensitive ovarian carcinoma:a gynecologic oncology group study [J].Gynecol Oncol,2003,89(1):95.
[22]Herbst R S, Hammond L A, Carbone D P, et al. A phase Ⅰ/ⅡA trial of continuous five-day infusion of squalamine lactate (MSI-1256F) plus carboplatin and paclitaxel in patients with advanced non-small cell lung cancer [J]. Clin Cancer Res,2003,9(11): 4108
[23]Mita A, Lockhart A C, Chen T L, et al. A phase Ⅰ pharmacokinetic (PK) trial of XAA296A (Discodermolide) administered every 3 wks to adult patients with advanced solid malignancies [C].J Clin Oncol,2004,22(14S):2025.
[24]Faircloth G, Cuevas C. Kahalalide F and ES285:potent anticancer agents from marine mollusks [J]. Prog Mol Subcell Biol,2006,43:363.
[25]Motohashi S, Ishikawa A, Ishikawa E, et al. A phase Ⅰ study of in vitro expanded natural killer T cells in patients with advanced and recurrent non-small cell lung cancer [J]. Clin Cancer Res,2006,12(20 Pt 1):6079.
[26]Rowinsky E K, de Bono J, Deangelo D J, et al. Cardiac monitoring in phase Ⅰ trials of a novel histone deacetylase (HDAC) inhibitor LAQ824 in patients with advanced solid tumors and hematologic malignancies [C].J Clin Oncol,2005, 23(16S):3131.
[27]Lam Kin S. Discovery of novel metabolites from marine actinomycetes[J]. Current Opinion in Microbiology,2006,9:245.
[28]E Erba, D Bergamaschi, S Ronzoni, et al. Mode of action of thiocoraline, a natural marine compound with anti-tumor activity[J]. Journal of Cancer,1999,80: 971.
[29]Li F C, Maskey R P, QinetBS, et al Chinikomycins A and B:isolation, structure elucidation, and biological activity of novel antibiotics from a marine Streptomyces sp. isolate M045[J]. J Nat Prod,2005,68(3):349.
[30]Maskey R, Helmke E, Kayser O, et al Marine bacteria XXVII. Helquinoline, a new tetrahydroquinoline antibiotic from Janibacter limosus Hel 1 [J] J. Antibiot,2004, 57:17.
[31]Maldonado L A, Fenical W, Jensen P R, et al. Salinispora arenicola gen. nov., sp. nov. and Salinispora tropica sp. nov., obligate marine actinomycetes belonging to the family Micromonosporaceae[J]. Int J Syst Evol Microbiol,2005,55:1759.
[32]Koike K, Sakamoto Y, Ohmoto T. A carbon-13 NMR study of β-carboline alkaloids [J]. Org Mag Resonan,1984,22(7):471.
[33]De Araujo-Junior V T, Da Silva M S, Da-Cunha E V L,et al. Alkaloids and diterpenes from Croton moritibensis [J]. Pharmaceut Biol,2004,42(1):62.
[34]Rahman A U, Hasan S, Qulbi M R.β-Carboline from Catharanthus roseus [J]. Planta Med,1985,50(3):287.
[35]孙朋悦,徐颖.朝鲜淫羊藿的化学成分Ⅱ[J].中国药物化学杂志,1998,8(4)：281.
[36]Adamczeski M, Reed A R, Crews P. New and known diketopiperazines from the Caribbean Sponge, Calyx cf. podatypa [J]. J Nat Prod,1995,58(2):201.
[37]Arunrattiyakorn P, Teruhiko N, Hiroshi K. Enzymatic conversion-based method for screening cyclic dipeptide-producing microbes [J]. Peptides,2006,27(4):633.
[38]Li Z Y, Peng C S, Lin H W, et al. L, L-Diketopiperazines from Alcaligenes faecalis A72 associated with South China Sea sponge Stelletta tenuis [J]. Biochem Syst Ecol,2008,36(3):230.
[39]曾雪容,焦伟华,唐金山,等.海洋放线菌Streptomyces sp. (No.30701)次生代谢产物研究[J].中国药物化学杂志,2010,20(4)：298.
[40]Lee D, Long S A, Adams J L, et al. Potent and selective nonpeptide inhibitors of caspases 3 and 7 inhibit apoptosis and maintain cell functionality [J]. J Biol Chem, 2000,275(21):16007.
[41]王元国.中草药ALN抗癌活性成分的研究[D].沈阳：沈阳药科大学,2004.
[42]高昊,陈国栋,唐金山等.一株海洋放线菌Bacillus sp. (No. DY1979)次生代谢产物研究[J].沈阳药科大学学报,2010,27(1)：69.
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