本文關(guān)鍵詞：海洋細(xì)菌抗膠質(zhì)瘤活性物質(zhì)的發(fā)現(xiàn)及生物活性研究　出處：《浙江大學(xué)》2017年博士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 海洋細(xì)菌 海洋鏈霉菌Streptomyces sp. 海洋放線菌Pseudonocardia sp.HS7 海洋天然產(chǎn)物 提取分離 結(jié)構(gòu)鑒定 抗膠質(zhì)瘤活性物質(zhì) 腫瘤細(xì)胞代謝酶

【摘要】：膠質(zhì)瘤是最常見和死亡率最高的腦腫瘤,多位于腦功能區(qū),手術(shù)切除極為困難,藥物對膠質(zhì)瘤的防治尤顯重要。傳統(tǒng)的第一代抗膠質(zhì)瘤藥和目前臨床上唯一可單獨(dú)用于膠質(zhì)瘤治療的金標(biāo)藥替莫唑胺均屬于細(xì)胞毒類烷化劑,具有毒副作用大和耐藥性等嚴(yán)重不足,臨床上迫切需要具有新作用機(jī)制的抗膠質(zhì)瘤新藥物。海洋微生物的次級代謝產(chǎn)物是抗膠質(zhì)瘤先導(dǎo)化合物的重要資源。本論文從多種海洋來源的樣品中分離得到了 255株海洋細(xì)菌,以抑制膠質(zhì)瘤細(xì)胞增殖為導(dǎo)向篩選獲得了 27株活性菌株;研究了其中5株放線菌(Streptomycesfradiae PTZ0025、Streptomyces sp.P11-23B、Pseudonocardiasp.HS7、Streptomycessp.Q24 和Streptomycessp.P83B)的化學(xué)成分及其抗膠質(zhì)瘤活性。應(yīng)用各種柱層析和HPLC,從這5株菌的培養(yǎng)物中分離到23個化合物,通過各種核磁共振譜、高分辨質(zhì)譜、二級質(zhì)譜和化學(xué)降解等相結(jié)合的方法鑒定了它們的化學(xué)結(jié)構(gòu),發(fā)現(xiàn)了 8 個新化合物,它們是:fradimycin A(2)、fradimycin B(3)、fradic acid A(5)、fradic acid B(6)、streptodepsipeptide P11A(8)、streptodepsipeptide P11B(9)、curvularin-7-O-α-D-glucopyranoside(12)和3-acetylamino-N-2-thienyl-propanamide(15)�？鼓z質(zhì)瘤活性研究發(fā)現(xiàn)了 18個化合物對膠質(zhì)瘤細(xì)胞的增殖均有抑制作用,其中化合物7、8、12、13、21和22這6個活性化合物還可明顯降低膠質(zhì)瘤U87-MG細(xì)胞不同代謝途徑關(guān)鍵酶的蛋白表達(dá)水平。非常有意義的是,這6個活性化合物分別是從可降低膠質(zhì)瘤細(xì)胞葡萄糖消耗和乳酸生成的3株放線菌(Streptomyces sp.P11-23B、Psuudonocardia sp.HS7和Streptomycessp.P83B)的培養(yǎng)物中獲得,提示,以抑制膠質(zhì)瘤增殖和影響膠質(zhì)瘤細(xì)胞葡萄糖消耗和乳酸生成為導(dǎo)向發(fā)現(xiàn)目標(biāo)活性化合物的意義和應(yīng)用前景。Streptodepsipeptide P11A(8)抗膠質(zhì)瘤活性強(qiáng)、對正常膠質(zhì)細(xì)胞毒性小,可誘導(dǎo)膠質(zhì)瘤U87-MG細(xì)胞凋亡和阻滯膠質(zhì)瘤U87-MG和U251細(xì)胞周期于Go/G1期。該化合物還可降低膠質(zhì)瘤U87-MG細(xì)胞乳酸生成和選擇性下調(diào)膠質(zhì)瘤U87-MG細(xì)胞不同代謝途徑的多個關(guān)鍵酶的蛋白表達(dá)水平,并促使膠質(zhì)瘤細(xì)胞代謝向正常細(xì)胞主導(dǎo)的氧化磷酸化途徑轉(zhuǎn)變。因此,新化合物8作為抗腫瘤先導(dǎo)化合物具有進(jìn)一步深入研究的價值。
[Abstract]:Glioma is the most common and the highest mortality brain tumors, mostly located in the brain functional areas, surgery is extremely difficult to remove. Traditional first-generation anti-glioma drugs and the only gold standard drug temozolamide which can be used in the treatment of glioma alone are cytotoxic alkylates. Has the toxic side effect big and the drug resistance and so on serious insufficiency. New anti-glioma drugs with new mechanism are urgently needed clinically. Secondary metabolites of marine microbes are important resources for antiglioma lead compounds. 255 strains of marine bacteria. A total of 27 active strains were obtained by targeting the inhibition of glioma cell proliferation. Five of them, Streptomyces fradiae PTZ0025, Streptomyces sp.P11-23B were studied. Pseudonocardiasp.HS7. The chemical constituents and anti-glioma activity of Streptomycessp.Q24 and Streptomyces sp. P83B were analyzed by various column chromatography and HPLC. Twenty-three compounds were isolated from the cultures of the 5 strains and their chemical structures were identified by means of nuclear magnetic resonance spectroscopy (NMR), high resolution mass spectrometry (HRMS), secondary mass spectrometry and chemical degradation. Eight new compounds were found. They are: fradimycin acid A5. Fradic acid 6, streptodepsipeptide P11A 8). Streptodepsipeptide P11BN9). Curvularin-7-O- 偽 -D-glucopyranoside 12). And 3-acetylamino-N-2-thienyl-propanamide15). 18 compounds were found to inhibit the proliferation of glioma cells. Among them, the six active compounds, 7, 8, 12, 12, 13, 13, 21 and 22, could significantly reduce the expression of key enzymes in different metabolic pathways of U87-MG cells. The six active compounds were isolated from three actinomycetes strains Streptomyces sp.P11-23B which could reduce glucose consumption and lactic acid production in glioma cells. Psuudonocardia sp.HS7 and Streptomyces sp. P83B). The significance and application prospect of target active compounds by inhibiting glioma proliferation and affecting glucose consumption and lactic acid production of glioma cells. P11A (. 8) strong anti-glioma activity. It has little toxicity to normal glial cells. It can induce apoptosis of U87-MG glioma cells and block the cell cycle of U87-MG and U251 glioma cells in Go/G1 phase. The compound can also reduce the production and selection of lactate in U87-MG glioma cells. The protein expression of several key enzymes in different metabolic pathways of U87-MG cells was down-regulated selectively. The metabolism of glioma cells was changed to the oxidative phosphorylation pathway dominated by normal cells. Therefore, the new compound 8 has the value of further research as a leading antitumor compound.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R915

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