請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/60595
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 梁碧惠(Pi-Hui Liang) | |
dc.contributor.author | Hsin-Min Hsiao | en |
dc.contributor.author | 蕭新民 | zh_TW |
dc.date.accessioned | 2021-06-16T10:22:48Z | - |
dc.date.available | 2018-09-24 | |
dc.date.copyright | 2013-09-24 | |
dc.date.issued | 2013 | |
dc.date.submitted | 2013-08-15 | |
dc.identifier.citation | 1 Riguera, R. Isolating bioactive compounds from marine organism. J. Mar. Biotechnol. 5, 187-193 (1997).
2 Vincken, J. P., Heng, L., de Groot, A., Gruppen, H. Saponins, classification and occurrence in the plant kingdom. Phytochemistry 68, 275-297, (2007). 3 Yu, B., Sun, J. Current synthesis of triterpene saponins. Chem. Asian J. 4, 642-654 (2009). 4 Park, J., Rhee, D., Lee, Y. Biological activities and chemistry of saponins from Panax ginseng C. A. Meyer. Phytochem. Rev. 4, 159-175 (2005). 5 Lanzotti, V. Bioactive saponins from Allium and Aster plants. Phytochem. Rev. 4, 95-110 (2005). 6 Kalinowska, M., Zimowski, J., Pączkowski, C., Wojciechowski, Z. A. The formation of sugar chains in triterpenoid saponins and glycoalkaloids. Phytochem. Rev. 4, 237-257 (2005). 7 Kalinin, V., Silchenko, A., Avilov, S., Stonik, V., Smirnov, A. Sea cucumbers triterpene glycosides, the recent progress in structural elucidation and Chemotaxonomy. Phytochem. Rev. 4, 221-236 (2005). 8 Francis, G., Kerem, Z., Makkar, H. P. S., Becker, K. The biological action of saponins in animal systems: a review. Br. J. Nutr. 88, 587-605 (2002). 9 Choi, S., Jung, S. Y., Kim, C. H., Kim, H. S., Rhim, H., Kim, S. C., Nah, S. Y. Effect of ginsenosides on voltage-dependent Ca2+ channel subtypes in bovine chromaffin cells. J. Ethnopharmacol. 74, 75-81 (2001). 10 Teodoro, T., Zhang, L., Alexander, T., Yue, J., Vranic, M., Volchuk, A. Oleanolic acid enhances insulin secretion in pancreatic beta-cells. FEBS Lett 582, 6 (2008). 11 Singh, G. B., Singh, S., Bani, S., Gupta, B. D., Banerjee, S. K. Anti-inflammatory activity of oleanolic acid in rats and mice. J. Pharm. Pharmacol. 44, 456-458 (1992). 12 Anisimov, M. M., Shcheglov, V. V., Strigina, L. I., Chetyrina, N. S., Uvarova, N. I., Oshitok, G. I., Alad'ina, N. G., Vecherko, L. P., Zorina, A. D., Matyukhina, L. G., Saltykova, I. A. Chemical structure and antifungal activity of a number of triterpenoids. Biol. Bull. Acad. Sci. USSR 6, 464-468 (1979). 13 Dai, Y., Hang, B. Q., Li, P. Z., Tan, L. W. Effects of oleanolic acid on immune system and type I allergic reaction. Zhongguo yao li xue bao 10, 381-384 (1989). 14 Dai, Y., Hang, B.Q., Tan, L.W. Anti-inflammatory effect of oleanolic acid. Chin. J. Pharmacol. Toxicol. 3, 96 (1989). 15 Zhou, C. C., Sun. X. B., Liu, L., Shi, H. B., Gao, H. B., Miao. Y. B. Effects of oleanolic acid on the immune complex allergic reaction and inflammation. J. Chin. Pharm. Sciences 2, 69 (1993). 16 Lee, W., Yang, E. J., Ku, S. K., Song, K. S., Bae, J. S. Anti-inflammatory effects of oleanolic acid on LPS-induced inflammation in vitro and in vivo. Inflammation 36, 94-102 (2013). 17 Klaassen, C. D., Reisman, S. A. Nrf2 the rescue: Effects of the antioxidative/electrophilic response on the liver. Toxicol. Appl. Pharmacol. 244, 57-65 (2010). 18 Liu, J., Wu, Q., Lu, Y. F., Pi, J. New insights into generalized hepatoprotective effects of oleanolic acid: key roles of metallothionein and Nrf2 induction. Biochem. Pharmacol. 76, 922-928 (2008). 19 Reisman, S. A., Aleksunes, L. M., Klaassen, C. D. Oleanolic acid activates Nrf2 and protects from acetaminophen hepatotoxicity via Nrf2-dependent and Nrf2-independent processes. Biochem. Pharmacol. 77, 1273-1282 (2009). 20 Hofmann, A. F. The continuing importance of bile acids in liver and intestinal disease. Arch. Intern. Med. 159, 2647-2658 (1999). 21 Liu, W., Wong, C. Oleanolic acid is a selective farnesoid X receptor modulator. Phytother. Res. 24, 369-373 (2010). 22 Liu, J. Pharmacology of oleanolic acid and ursolic acid. J. Ethnopharmacol 49, 57-68 (1995). 23 Wei, J., Liu, M., Liu, H., Wang, H., Wang, F., Zhang, Y., Han, L., Lin, X. Oleanolic acid arrests cell cycle and induces apoptosis via ROS-mediated mitochondrial depolarization and lysosomal membrane permeabilization in human pancreatic cancer cells. J. Appl. Toxicol. 33, 756-765 (2013). 24 Liby, K. T., Sporn, M. B. Synthetic oleanane triterpenoids: multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease. Pharmacol. Rev. 64, 972-1003 (2012). 25 Leal, A. S., Wang, R., Salvador, J. A., Jing, Y. Synthesis of novel heterocyclic oleanolic acid derivatives with improved antiproliferative activity in solid tumor cells. Org. Biomol. Chem. 11, 1726-1738 (2013). 26 Moreira, V. M., Salvador, J. A., Simoes, S., Destro, F., Gavioli, R. Novel oleanolic vinyl boronates: Synthesis and antitumor activity. Eur. J. Med. Chem. 63, 46-56 (2013). 27 Fujioka, T., Kashiwada, Y., Okabe, H., Mihashi, K., Lee, K. H. Antitumor agents 171. Cytotoxicities of lobatosides B, C, D, and E, cyclic bisdesmosides isolated from Actinostemma lobatum maxim. Bioorg. Med. Chem. Lett. 6, 2807-2810 (1996). 28 Chaturvedula, V. S., Schilling, J. K., Miller, J. S., Andriantsiferana, R., Rasamison, V. E., Kingston, D. G. New cytotoxic oleanane saponins from the infructescences of Polyscias amplifolia from the Madagascar rainforest. Planta Med. 69, 440-444 (2003). 29 Khan, I. A., Clark, A. M., McChesney, J. D. Antifungal activity of a new triterpenoid glycoside from Pithecellobium racemosum (M.). Pharm. Res. 14, 358-361 (1997). 30 Seo, Y., Hoch, J., Abdel-Kader, M., Malone, S., Derveld, I., Adams, H., Werkhoven, M. C., Wisse, J. H., Mamber, S. W., Dalton, J. M., Kingston, D. G. Bioactive saponins from Acacia tenuifolia from the suriname rainforest. J. Nat. Prod. 65, 170-174 (2002). 31 Abdel-Kader, M., Hoch, J., Berger, J. M., Evans, R., Miller, J. S., Wisse, J. H., Mamber, S. W., Dalton, J. M., Kingston, D. G. I. Two bioactive saponins from Albizia subdimidiata from the suriname rainforest1. J. Nat. Prod. 64, 536-539 (2001). 32 Hamed, A. I., Piacente, S., Autore, G., Marzocco, S., Pizza, C., Oleszek, W. Antiproliferative hopane and oleanane glycosides from the roots of Glinus lotoides. Planta Med. 71, 554-560 (2005). 33 Melek, F. R., Miyase, T., Ghaly, N. S., Nabil, M. Triterpenoid saponins with N-acetyl sugar from the bark of Albizia procera. Phytochemistry 68, 1261-1266, (2007). 34 Wang, P., Wang, J., Guo, T., Li, Y. Synthesis and cytotoxic activity of the N-acetylglucosamine-bearing triterpenoid saponins. Carbohydr. Res. 345, 607-620 (2010). 35 Zeng, Y. B. Synthesis Library of N-Acetylglucosamine-bearing oleanolic acid and their anticancer activity. National Taiwan University, Master Thesis ; Dec (2013). 36 Varasteh, Z., Velikyan, I., Lindeberg, G., Sorensen, J., Larhed, M., Sandstrom, M., Selvaraju, R. K., Malmberg, J., Tolmachev, V., Orlova, A. Synthesis and characterization of a high-affinity NOTA-conjugated bombesin antagonist for GRPR-targeted tumor imaging. Bioconjug. Chem. 24, 1144-1153 (2013). 37 Di Gialleonardo, V., Signore, A., Scheerstra, E. A., Visser, A. K. D., van Waarde, A., O Dierckx, R. A. J., de Vries, E. F. J. 11C-Hydroxytryptophan uptake and metabolism in endocrine and exocrine pancreas. J. Nucl. Med. 53, 1755-1763 (2012). 38 Li, Y., Wang, X., Zhang, J., Deuther-Conrad, W., Xie, F., Zhang, X., Liu, J., Qiao, J., Cui, M., Steinbach, J., Brust, P., Liu, B., Jia, H. Synthesis and evaluation of novel 18F-labeled spirocyclic piperidine derivatives as σ1 receptor ligands for positron emission tomography imaging. J. Med. Chem. 56, 3478-3491 (2013). 39 Matijašić, M., Munić Kos, V., Nujić, K., Čužić, S., Padovan, J., Kragol, G., Alihodžić, S., Mildner, B., Verbanac, D., Eraković Haber, V. Fluorescently labeled macrolides as a tool for monitoring cellular and tissue distribution of azithromycin. Pharmacol. Res. 66, 332-342 (2012). 40 Thurber, G. M.; Yang, K. S.; Reiner, T.; Kohler, R. H.; Sorger, P.; Mitchison, T.; Weissleder, R. Single-cell and subcellular pharmacokinetic imaging allows insight into drug action in vivo. Nat. Commun. 4, 1504 (2013). 41 Dai, C. F., Mangiardi, D., Cotanche, D. A., Steyger, P. S. Uptake of fluorescent gentamicin by vertebrate sensory cells in vivo. Hear. Res. 213, 64-78 (2006). 42 Cravatt, B. F., Sorensen, E. J. Chemical strategies for the global analysis of protein function. Curr. Opin. Chem. Biol. 4, 663-668 (2000). 43 Johnsson, N., Johnsson, K. A Fusion of Disciplines: Chemical approaches to exploit fusion proteins for functional genomics. ChemBioChem 4, 803-810 (2003). 44 Saxon, E., Bertozzi, C. R. Cell surface engineering by a modified staudinger reaction. Science 287, 2007-2010 (2000). 45 Bock, V. D., Hiemstra, H., van Maarseveen, J. H. CuI-catalyzed alkyne–azide “click” cycloadditions from a mechanistic and synthetic perspective. European J. Org. Chem. 2006, 51-68 (2006). 46 Wang, Q., Chan, T. R., Hilgraf, R., Fokin, V. V., Sharpless, K. B., Finn, M. Bioconjugation by copper(I)-catalyzed azide-alkyne [3 + 2] cycloaddition. J. Am. Chem. Soc. 125, 3192-3193 (2003). 47 Agard, N. J., Prescher, J. A., Bertozzi, C. R. A strain-promoted [3 + 2] azide−alkyne cycloaddition for covalent modification of biomolecules in living systems. J. Am. Chem. Soc. 126, 15046-15047 (2004). 48 Mbua, N. E., Guo, J., Wolfert, M. A., Steet, R., Boons, G. J. Strain-promoted alkyne–azide cycloadditions (SPAAC) reveal new features of glycoconjugate biosynthesis. ChemBioChem 12, 1912-1921 (2011). 49 Koo, H., Lee, S., Na, J. H., Kim, S. H., Hahn, S. K., Choi, K., Kwon, I. C., Jeong, S. Y., Kim, K. Bioorthogonal copper-free click chemistry in vivo for tumor-targeted delivery of nanoparticles. Angew. Chem. Int. Ed. Engl. 51, 11836-11840 (2012). 50 Laughlin, S. T., Baskin, J. M., Amacher, S. L., Bertozzi, C. R. In vivo imaging of membrane-associated glycans in developing zebrafish. Science 320, 664-667 (2008). 51 Willems, L. I., Verdoes, M., Florea, B. I., van der Marel, G. A., Overkleeft, H. S. Two-step labeling of endogenous enzymatic activities by diels–alder ligation. ChemBioChem 11, 1769-1781 (2010). 52 Lang, K., Davis, L., Wallace, S., Mahesh, M., Cox, D. J., Blackman, M. L., Fox, J. M., Chin, J. W. Genetic encoding of bicyclononynes and trans-cyclooctenes for site-specific protein labeling in vitro and in live mammalian cells via rapid fluorogenic diels–alder reactions. J. Am. Chem. Soc. 134, 10317-10320 (2012). 53 Niederwieser, A., Spate, A. K., Nguyen, L. D., Jungst, C., Reutter, W., Wittmann, V. Two-color glycan labeling of live cells by a combination of diels–alder and click chemistry. Angew. Chem. Int. Ed. Engl. 52, 4265-4268 (2013). 54 Hori, Y., Kikuchi, K. Protein labeling with fluorogenic probes for no-wash live-cell imaging of proteins. Curr. Opin. Chem. Biol. 17, 644-650 (2013). 55 Griffin, B. A., Adams, S. R., Tsien, R. Y. Specific covalent labeling of recombinant protein molecules inside live cells. Science 281, 269-272 (1998). 56 Levine, M. N., Hoang, T. T., Raines, R. T. Fluorogenic probe for constitutive cellular endocytosis. Chem. Biol. 20, 614-618 (2013). 57 Le Droumaguet, C., Wang, C., Wang, Q. Fluorogenic click reaction. Chem. Soc. Rev. 39, 1233-1239 (2010). 58 Sivakumar, K., Xie, F., Cash, B. M., Long, S., Barnhill, H. N., Wang, Q. A fluorogenic 1,3-dipolar cycloaddition reaction of 3-azidocoumarins and acetylenes†. Org. Lett. 6, 4603-4606 (2004). 59 Sawa, M., Hsu, T. L., Itoh, T., Sugiyama, M., Hanson, S. R., Vogt, P. K., Wong, C. H. Glycoproteomic probes for fluorescent imaging of fucosylated glycans in vivo. Proc. Nat. Acad. Sci.USA 103, 12371-12376 (2006). 60 Xie, F., Sivakumar, K., Zeng, Q., Bruckman, M. A., Hodges, B., Wang, Q. A fluorogenic ‘click’ reaction of azidoanthracene derivatives. Tetrahedron 64, 2906-2914 (2008). 61 Qi, J., Han, M.-S., Chang, Y. C., Tung, C. H. Developing visible fluorogenic ‘click-on’ dyes for cellular imaging. Bioconjug. Chem. 22, 1758-1762 (2011). 62 Shieh, P., Hangauer, M. J., Bertozzi, C. R. Fluorogenic azidofluoresceins for biological imaging. J. Am. Chem. Soc. 134, 17428-17431 (2012). 63 Yan, M. C., Liu, Y., Chen, H., Ke, Y., Xu, Q. C., Cheng, M. S. Synthesis and antitumor activity of two natural N-acetylglucosamine-bearing triterpenoid saponins: Lotoidoside D and E. Bioorg. Med. Chem. Lett. 16, 4200-4204 (2006). 64 Sun, J., Han, X., Yu, B. Synthesis of a typical N-acetylglucosamine-containing saponin, oleanolic acid 3-yl α-l-arabinopyranosyl-(1→2)-α-l-arabinopyranosyl-(1→6)-2-acetamido-2-deoxy-β-d-glucopyranoside. Carbohydr. Res. 338, 827-833 (2003). 65 Ellervik, U., Magnusson, G. Glycosylation with N-Troc-protected glycosyl donors. Carbohydr. Res. 280, 251-260 (1996). 66 Liu, H., Wong, C. H. Characterization of a transglycosylase domain of Streptococcus pneumoniae PBP1b. Bioorg. Med. Chem. 14, 7187-7195 (2006). 67 Grann Hansen, S., Skrydstrup, T. Studies directed to the synthesis of oligochitosans – preparation of building blocks and their evaluation in glycosylation studies. European J. Org. Chem. 2007, 3392-3401 (2007). 68 Ishikawa, T., Zhu, B. L., Maeda, H. Effect of sodium azide on the metabolic activity of cultured fetal cells. Toxicol. Ind. Health 22, 337-341 (2006). | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/60595 | - |
dc.description.abstract | 從天然物中分離出三萜類以及固醇類皂素具有多樣的生物活性,包括抗感染、免疫調節以及細胞毒性等等。而根據已有的文獻指出,屬三萜類皂素的齊墩果酸,其攜帶N-乙醯葡萄醣胺之配醣體對於腫瘤細胞上有顯著的活性。而在我們先前的研究中發現將葡萄醣胺的胺基位置從乙醯胺變為methoxy carbamate,會造成其抗癌活性的改變,因此我們在這個研究中,合成一系列葡萄醣胺上由不同碳鏈長度的醯胺以及carbamate修飾的齊墩果酸衍生物,並檢測其抗癌活性。
為製備這類衍生物,我們分別合成核心結構83以及95。化合物83以醇類加上4.0 N的NaOH反應而得到2號位置為不同碳鏈長的carbamate衍生物87–89。而化合物95則以ethylenediamine去除Phth的保護後,加入不同的酸酐或是用酸加上偶合試劑使胺基上形成帶不同碳鏈長度的醯胺鍵,而得到化合物40、103–107、以及111–113。 我們將這些化合物對血癌細胞株HL-60進行生長抑制的實驗,發現化合物88、106、107、111–114可有小於10 μM 的IC50。在所有化合物中以帶有癸醯胺的113的活性最佳 (IC50 = 3.0)。而由細胞週期實驗的結果,可發現細胞DNA碎裂成片段,顯示這類化合物在抑制HL-60的生長時是確實造成細胞的死亡而非只是使細胞的生長停滯。 為了觀察到藥物在細胞內的分佈,我們將帶有炔鍵的化合物114加入細胞中培養,之後加入fluorogenic azido-coumarin 115來進行Cu[I]-catalyzed [3+2] cycloaddition,此反應又稱click chemistry。在我們的細胞影像實驗上,可看到114非常專一地分佈在細胞核中,而同時也可看到細胞核破裂的現象,此觀察結果與細胞週期實驗的結果一致。此實驗也提供了一個可直接觀察藥物在細胞內分佈的方法,對於細胞內藥物機轉的研究會有所幫助。 | zh_TW |
dc.description.provenance | Made available in DSpace on 2021-06-16T10:22:48Z (GMT). No. of bitstreams: 1 ntu-102-R00423019-1.pdf: 5795611 bytes, checksum: d40ef2c4b1114afbfc10ff5c0ff98005 (MD5) Previous issue date: 2013 | en |
dc.description.tableofcontents | 目 錄
中文摘要 I Abstracts II 圖目錄 VI 路徑目錄 VII 表目錄 VII 縮寫表 VIII 一、研究背景: 1 1.1 皂素 (saponin) 之介紹 1 1.2 奇墩果酸 (oleanolic acid) 2 1.3 齊墩果酸類皂素抗癌活性之研究 4 1.4 藥物影像偵測 13 1.5 Bioorthogonal labeling及其在細胞影像之應用 14 1.6 Fluorogenic probe之介紹 18 1.7 研究動機 21 二、結果與討論 23 2.1 化學合成方法 23 2.1.1 Benzyl oleanolate 之製備 23 2.1.2 carbamate修飾之齊墩果酸配醣體的合成 24 2.1.3 Amide bond修飾之齊墩果酸配醣體的合成 27 2.1.4 含Alkyne group之齊墩果酸配醣體之合成 31 2.1.5 3-Azido-7-hydroxycoumarin (116) 之合成 34 2.2 生物活性 35 2.2.1 抗癌活性及SAR探討 35 2.2.2 細胞週期實驗 37 2.2.3 細胞影像結果 38 三、結論 40 四、實驗部分 41 4.1 實驗試劑及儀器來源 41 4.2 合成步驟與數據 44 4.3 生物實驗 76 4.3.1 MTT assay 76 4.3.2 Cell cycle experiments 76 4.3.3 Cell imaging experiments 77 五、參考文獻 78 六、附圖 86 | |
dc.language.iso | zh-TW | |
dc.title | 針對醯胺修飾之葡萄糖胺齊墩果酸的合成與抗癌藥理活性探討 | zh_TW |
dc.title | Synthesis and Pharmacology of Amide Modifications on Glucosamine-Bearing Oleanolic Acid as Anticancer Agents | en |
dc.type | Thesis | |
dc.date.schoolyear | 101-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 李水盛,顧記華,蒙國光,鄭偉杰 | |
dc.subject.keyword | 齊墩果酸,葡萄糖胺, | zh_TW |
dc.subject.keyword | Oleanolic acid,glucosamine, | en |
dc.relation.page | 120 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2013-08-16 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥學研究所 | zh_TW |
顯示於系所單位: | 藥學系 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-102-1.pdf 目前未授權公開取用 | 5.66 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。