Please use this identifier to cite or link to this item:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78767Full metadata record
| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 梁碧惠 | |
| dc.contributor.author | Chee-Wai Chaw | en |
| dc.contributor.author | 刁志威 | zh_TW |
| dc.date.accessioned | 2021-07-11T15:17:55Z | - |
| dc.date.available | 2021-08-31 | |
| dc.date.copyright | 2019-08-28 | |
| dc.date.issued | 2019 | |
| dc.date.submitted | 2019-07-17 | |
| dc.identifier.citation | 1. Sparg, S. G.; Light, M. E.; van Staden, J., Biological activities and distribution of plant saponins. J. Ethnopharmacol. 2004, 94, 219-243.
2. Augustin, J. M.; Kuzina, V.; Andersen, S. B.; Bak, S., Molecular activities, biosynthesis and evolution of triterpenoid saponins. Phytochemistry 2011, 72, 435-457. 3. Köhler, H., Kohler's Medicinal Plants. Gera, Germany: Gera-Untermhaus 1887. 4. Fleck, J. D.; Betti, A. H.; da Silva, F. P.; Troian, E. A.; Olivaro, C.; Ferreira, F.; Verza, S. G., Saponins from Quillaja saponaria and Quillaja brasiliensis: Particular Chemical Characteristics and Biological Activities. Molecules 2019, 24, 171. 5. Guo, S.; Kenne, L.; Lundgren, L. N.; Ronnberg, B.; Sundquist, B. G., Triterpenoid saponins from Quillaja saponaria. Phytochemistry 1998, 48, 175-180. 6. Kite, G. C.; Howes, M. J.; Simmonds, M. S., Metabolomic analysis of saponins in crude extracts of Quillaja saponaria by liquid chromatography/mass spectrometry for product authentication. Rapid Commun. Mass Spectrom. 2004, 18, 2859-2870. 7. Alimentarius, C., Codex Alimentarius: international food standards. Retrieved from Prevention and reduction of food and feed contamination: http://www.codexalimentarius.org/download/standards/11257/CXP_068e.pdf 2015. 8. de Faria, J. T.; de Oliveira, E. B.; Minim, V. P. R.; Minim, L. A., Performance of Quillaja bark saponin and β-lactoglobulin mixtures on emulsion formation and stability. Food Hydrocolloid. 2017, 67, 178-188. 9. Roner, M. R.; Tam, K. I.; Kiesling-Barrager, M., Prevention of rotavirus infections in vitro with aqueous extracts of Quillaja Saponaria Molina. Future Med. Chem. 2010, 2, 1083-1097. 10. Dixit, V.; Tewari, J.; Obendorf, S. K., Fungal growth inhibition of regenerated cellulose nanofibrous membranes containing Quillaja saponin. Arch. Environ. Contam. Toxicol. 2010, 59, 417-423. 11. Holtshausen, L.; Chaves, A. V.; Beauchemin, K. A.; McGinn, S. M.; McAllister, T. A.; Odongo, N. E.; Cheeke, P. R.; Benchaar, C., Feeding saponin-containing Yucca schidigera and Quillaja saponaria to decrease enteric methane production in dairy cows. J. Dairy Sci. 2009, 92, 2809-2821. 12. Ahmed Abdel-Reheim, M.; Messiha, B. A. S.; Abo-Saif, A. A., Quillaja saponaria bark saponin protects Wistar rats against ferrous sulphate-induced oxidative and inflammatory liver damage. Pharm. Biol. 2017, 55, 1972-1983. 13. Higuchi, R.; Tokimitsu, Y.; Komori, T., An acylated triterpenoid saponin from Quillaja Saponaria. Phytochemistry 1988, 27, 1165-1168. 14. Nord, L. I.; Kenne, L., Novel acetylated triterpenoid saponins in a chromatographic fraction from Quillaja saponaria Molina. Carbohydr. Res. 2000, 329, 817-829. 15. Wallace, F.; Bennadji, Z.; Ferreira, F.; Olivaro, C., Analysis of an immunoadjuvant saponin fraction from Quillaja brasiliensis leaves by electrospray ionization ion trap multiple-stage mass spectrometry. Phytochem. Lett. 2017, 20, 228-233. 16. Lu, Y.; Van, D.; Deibert, L.; Bishop, G.; Balsevich, J., Antiproliferative quillaic acid and gypsogenin saponins from Saponaria officinalis L. roots. Phytochemistry 2015, 113, 108-120. 17. Takahashi, N.; Li, W.; Koike, K., Oleanane-type triterpenoid saponins from Silene armeria. Phytochemistry 2016, 129, 77-85. 18. De Costa, F.; CA Yendo, A.; D Fleck, J.; Gosmann, G.; G Fett-Neto, A., Immunoadjuvant and anti-inflammatory plant saponins: characteristics and biotechnological approaches towards sustainable production. Mini-rev. Med. Chem. 2011, 11, 857-880. 19. San Martin, R., Sustainable Production of Quillaja Saponaria Mol. Saponins. In Saponins in Food, Feedstuffs and Medicinal Plants, Oleszek, W.; Marston, A., Eds. Springer Netherlands: Dordrecht 2000, 271-279. 20. Dalsgaard, K., Saponin adjuvants. 3. Isolation of a substance from Quillaja saponaria Molina with adjuvant activity in food-and-mouth disease vaccines. Arch. Gesamte Virusforsch 1974, 44, 243-254. 21. Ebbesen, P.; Dalsgaard, K.; Madsen, M., Prolonged survival of AKR mice treated with the saponin adjuvant Quil A. Acta. Pathol. Microbiol. Scand. A. 1976, 84, 358-360. 22. Hu, K.; Berenjian, S.; Larsson, R.; Gullbo, J.; Nygren, P.; Lovgren, T.; Morein, B., Nanoparticulate Quillaja saponin induces apoptosis in human leukemia cell lines with a high therapeutic index. Int. J. Nanomedicine 2010, 5, 51-62. 23. Reed, S. G.; Orr, M. T.; Fox, C. B., Key roles of adjuvants in modern vaccines. Nat. Med. 2013, 19, 1597-1608. 24. Sun, H. X.; Xie, Y.; Ye, Y. P., Advances in saponin-based adjuvants. Vaccine 2009, 27, 1787-1796. 25. Rajput, Z. I.; Hu, S. H.; Xiao, C. W.; Arijo, A. G., Adjuvant effects of saponins on animal immune responses. J. Zhejiang Univ. Sci. B 2007, 8, 153-161. 26. Egerton, J.; Laing, E.; Thorley, C., Effect of Quil A, a saponin derivative, on the response of sheep to alum precipitated Bacteroides nodosus vaccines. Vet. Sci. Commun. 1978, 2, 247-252. 27. Kensil, C. R.; Patel, U.; Lennick, M.; Marciani, D., Separation and characterization of saponins with adjuvant activity from Quillaja saponaria Molina cortex. J. Immunol. 1991, 146, 431-437. 28. Ragupathi, G.; Gardner, J. R.; Livingston, P. O.; Gin, D. Y., Natural and synthetic saponin adjuvant QS-21 for vaccines against cancer. Expert Rev. Vaccines. 2011, 10, 463-470. 29. Soltysik, S.; Wu, J. Y.; Recchia, J.; Wheeler, D. A.; Newman, M. J.; Coughlin, R. T.; Kensil, C. R., Structure/function studies of QS-21 adjuvant: assessment of triterpene aldehyde and glucuronic acid roles in adjuvant function. Vaccine 1995, 13, 1403-1410. 30. Kensil, C. R.; Wu, J. Y.; Anderson, C. A.; Wheeler, D. A.; Amsden, J., QS-21 and QS-7: purified saponin adjuvants. Dev. Biol. Stand. 1998, 92, 41-47. 31. Deng, K.; Adams, M. M.; Gin, D. Y., Synthesis and structure verification of the vaccine adjuvant QS-7-Api. Synthetic access to homogeneous Quillaja Saponaria immunostimulants. J. Am. Chem. Soc. 2008, 130, 5860-5861. 32. Wang, P.; Skalamera, D.; Sui, X.; Zhang, P.; Michalek, S. M., Synthesis and Evaluation of a QS-17/18-Based Vaccine Adjuvant. J. Med. Chem. 2019, 62, 1669-1676. 33. Tomori, O., From smallpox eradication to the future of global health: innovations, application and lessons for future eradication and control initiatives. Vaccine 2011, 29, 145-148. 34. Kaufmann, S. H.; Weiner, J.; von Reyn, C. F., Novel approaches to tuberculosis vaccine development. Int. J. Infect. Dis. 2017, 56, 263-267. 35. Toole, M. J., So close: remaining challenges to eradicating polio. BMC Med. 2016, 14, 43. 36. Cernuschi, T.; Malvolti, S.; Nickels, E.; Friede, M., Bacillus Calmette-Guerin (BCG) vaccine: A global assessment of demand and supply balance. Vaccine 2018, 36, 498-506. 37. Baz, M.; Luke, C. J.; Cheng, X.; Jin, H.; Subbarao, K., H5N1 vaccines in humans. Virus Res. 2013, 178, 78-98. 38. McKee, A. S.; Marrack, P., Old and new adjuvants. Curr. Opin. Immunol. 2017, 47, 44-51. 39. Lindblad, E. B., Aluminium adjuvants--in retrospect and prospect. Vaccine 2004, 22, 3658-3668. 40. Brewer, J. M., (How) do aluminium adjuvants work? Immunol. Lett. 2006, 102, 10-15. 41. Del Giudice, G.; Rappuoli, R.; Didierlaurent, A. M., Correlates of adjuvanticity: A review on adjuvants in licensed vaccines. Semin. Immunol. 2018, 39, 14-21. 42. Morel, S.; Didierlaurent, A.; Bourguignon, P.; Delhaye, S.; Baras, B.; Jacob, V.; Planty, C.; Elouahabi, A.; Harvengt, P.; Carlsen, H.; Kielland, A.; Chomez, P.; Garcon, N.; Van Mechelen, M., Adjuvant System AS03 containing alpha-tocopherol modulates innate immune response and leads to improved adaptive immunity. Vaccine 2011, 29, 2461-2473. 43. Singh, M.; O'Hagan, D. T., Recent advances in veterinary vaccine adjuvants. Int. J. Parasitol. 2003, 33, 469-478. 44. Song, X.; Hu, S., Adjuvant activities of saponins from traditional Chinese medicinal herbs. Vaccine 2009, 27, 4883-4890. 45. Kensil, C. R.; Kammer, R., QS-21: a water-soluble triterpene glycoside adjuvant. Expert Opin. Investig. Drugs 1998, 7, 1475-1482. 46. Katayama, S.; Oda, K.; Ohgitani, T.; Hirahara, T.; Shimizu, Y., Influence of antigenic forms and adjuvants on the IgG subclass antibody response to Aujeszky's disease virus in mice. Vaccine 1999, 17, 2733-2739. 47. O'Hagan, D. T.; MacKichan, M. L.; Singh, M., Recent developments in adjuvants for vaccines against infectious diseases. Biomol. Eng. 2001, 18, 69-85. 48. Liu, G.; Anderson, C.; Scaltreto, H.; Barbon, J.; Kensil, C. R., QS-21 structure/function studies: effect of acylation on adjuvant activity. Vaccine 2002, 20, 2808-2815. 49. Garcon, N.; Di Pasquale, A., From discovery to licensure, the Adjuvant System story. Hum. Vacc. Immunother. 2017, 13, 19-33. 50. Olotu, A.; Fegan, G.; Wambua, J.; Nyangweso, G.; Leach, A.; Lievens, M.; Kaslow, D. C.; Njuguna, P.; Marsh, K.; Bejon, P., Seven-Year Efficacy of RTS, S/AS01 Malaria Vaccine among Young African Children. N. Engl. J. Med. 2016, 374, 2519-2529. 51. Tinto, H.; D'Alessandro, U.; Sorgho, H.; Valea, I.; Tahita, M. C.; Kabore, W.; Kiemde, F.; Lompo, P.; Ouedraogo, S.; Derra, K.; Ouedraogo, F.; Ouedraogo, J. B.; Ballou, W. R.; Cohen, J.; Guerra, Y.; Heerwegh, D.; Jongert, E.; Lapierre, D.; Leach, A.; Lievens, M.; Ofori-Anyinam, O.; Olivier, A.; Vekemans, J.; Agnandji, S. T.; Lell, B.; Fernandes, J. F.; Abossolo, B. P.; Kabwende, A. L.; Adegnika, A. A.; Mordmuller, B.; Issifou, S.; Kremsner, P. G.; Loembe, M. M.; Bache, E.; Alabi, A.; Owusu-Agyei, S.; Asante, K. P.; Boahen, O.; Dosoo, D.; Asante, I.; Yidana, Z.; Anim, J.; Adeniji, E.; Yawson, A. K.; Kayan, K.; Chandramohan, D.; Greenwood, B.; Ansong, D.; Agbenyega, T.; Adjei, S.; Boateng, H. O.; Rettig, T.; Sylverken, J.; Sambian, D.; Badu-Prepah, A.; Kotey, A.; Buabeng, P.; Paintsil, V.; Enimil, A.; Hamel, M. J.; Kariuki, S.; Oneko, M.; Odero, C.; Otieno, K.; Awino, N.; Muturi-Kioi, V.; Omoto, J.; Sang, T.; Odhiambo, S.; Laserson, K. F.; Slutsker, L.; Otieno, W.; Otieno, L.; Otsyula, N.; Gondi, S.; Ochola, J.; Okoth, G.; Mabunde, D. C.; Wangwe, A.; Otieno, A.; Oyieko, J.; Cowden, J.; Ogutu, B.; Njuguna, P.; Marsh, K.; Akoo, P.; Kerubo, C.; Maingi, C.; Bejon, P.; Olotu, A.; Chilengi, R.; Tsofa, B.; Lang, T.; Gitaka, J.; Awuondo, K.; Martinson, F.; Hoffman, I.; Mvalo, T.; Kamthunzi, P.; Nkomo, R.; Tembo, T.; Tegha, G.; Chawinga, C.; Banda, T.; Khan, S.; Mwambakulu, S.; Mzembe, E.; Sacarlal, J.; Aide, P.; Madrid, L.; Mandjate, S.; Aponte, J. J.; Bulo, H.; Massora, S.; Varela, E.; Macete, E.; Alonso, P.; Lusingu, J.; Gesase, S.; Malabeja, A.; Abdul, O.; Mahende, C.; Liheluka, E.; Lemnge, M.; Theander, T. G.; Drakeley, C.; Mbwana, J.; Olomi, R.; Mmbando, B.; Abdulla, S.; Salim, N.; Mtoro, A.; Ahmed, S.; Hamad, A.; Kafuruki, S.; Minja, R.; Tanner, M.; Maganga, M.; Mdemu, A.; Gwandu, C.; Mohammed, A.; Kaslow, D.; Leboulleux, D.; Savarese, B.; Schellenberg, D.; Partnership, R. S. C. T., Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet 2015, 386, 31-45. 52. Eggermont, A. M. M.; Suciu, S.; Rutkowski, P.; Marsden, J.; Santinami, M.; Corrie, P.; Aamdal, S.; Ascierto, P. A.; Patel, P. M.; Kruit, W. H.; Bastholt, L.; Borgognoni, L.; Bernengo, M. G.; Davidson, N.; Polders, L.; Praet, M.; Spatz, A., Adjuvant Ganglioside GM2-KLH/QS-21 vaccination versus observation after resection of primary tumor > 1.5 mm in patients with stage II melanoma: results of the EORTC 18961 randomized phase III trial. J. Clin. Oncol. 2013, 31, 3831. 53. Hull, M.; Sadowsky, C.; Arai, H.; Le Prince Leterme, G.; Holstein, A.; Booth, K.; Peng, Y.; Yoshiyama, T.; Suzuki, H.; Ketter, N.; Liu, E.; Ryan, J. M., Long-Term Extensions of randomized vaccination trials of ACC-001 and QS-21 in mild to moderate Alzheimer's disease. Curr. Alzheimer Res. 2017, 14, 696-708. 54. Pasquier, F.; Sadowsky, C.; Holstein, A.; Leterme, G. L. P.; Peng, Y.; Jackson, N.; Fox, N. C.; Ketter, N.; Liu, E.; Ryan, J. M., Two phase 2 multiple ascending–dose studies of Vanutide Cridificar (ACC-001) and QS-21 adjuvant in mild-to-moderate Alzheimer’s disease. J. Alzheimers Dis. 2016, 51, 1131-1143. 55. Marciani, D. J., Elucidating the mechanisms of action of saponin-derived adjuvants. Trends Pharmacol. Sci. 2018, 39, 573-585. 56. Chea, E. K.; Fernandez-Tejada, A.; Damani, P.; Adams, M. M.; Gardner, J. R.; Livingston, P. O.; Ragupathi, G.; Gin, D. Y., Synthesis and preclinical evaluation of QS-21 variants leading to simplified vaccine adjuvants and mechanistic probes. J. Am. Chem. Soc. 2012, 134, 13448-13457. 57. Fernandez-Tejada, A.; Chea, E. K.; George, C.; Pillarsetty, N.; Gardner, J. R.; Livingston, P. O.; Ragupathi, G.; Lewis, J. S.; Tan, D. S.; Gin, D. Y., Development of a minimal saponin vaccine adjuvant based on QS-21. Nat. Chem. 2014, 6, 636-644. 58. Švajger, U.; Anderluh, M.; Jeras, M.; Obermajer, N., C-type lectin DC-SIGN: an adhesion, signalling and antigen-uptake molecule that guides dendritic cells in immunity. Cellular signalling 2010, 22, 1397-1405. 59. Marciani, D. J., Is fucose the answer to the immunomodulatory paradox of Quillaja saponins? Int. immunopharmacol. 2015, 29, 908-913. 60. Marciani, D. J.; Pathak, A. K.; Reynolds, R. C.; Seitz, L.; May, R. D., Altered immunomodulating and toxicological properties of degraded Quillaja saponaria Molina saponins. Int. Immunopharmacol 2001, 1, 813-818. 61. Press, J. B.; Reynolds, R. C.; May, R. D.; Marciani, D. J., Structure/function relationships of immunostimulating saponins. In Studies in Natural Products Chemistry, Elsevier: 2000; 24, 131-174. 62. den Brok, M. H.; Bull, C.; Wassink, M.; de Graaf, A. M.; Wagenaars, J. A.; Minderman, M.; Thakur, M.; Amigorena, S.; Rijke, E. O.; Schrier, C. C.; Adema, G. J., Saponin-based adjuvants induce cross-presentation in dendritic cells by intracellular lipid body formation. Nat. Commun. 2016, 7, 13324. 63. Lorent, J. H.; Quetin-Leclercq, J.; Mingeot-Leclercq, M. P., The amphiphilic nature of saponins and their effects on artificial and biological membranes and potential consequences for red blood and cancer cells. Org. Biomo.l Chem. 2014, 12, 8803-8822. 64. Livingston, P. O.; Adluri, S.; Helling, F.; Yao, T. J.; Kensil, C. R.; Newman, M. J.; Marciani, D., Phase 1 trial of immunological adjuvant QS-21 with a GM2 ganglioside-keyhole limpet haemocyanin conjugate vaccine in patients with malignant melanoma. Vaccine 1994, 12, 1275-1280. 65. Zhu, D.; Tuo, W., QS-21: A Potent Vaccine Adjuvant. Nat. Prod. Chem. Res. 2016, 3. 66. San Martín, R.; Briones, R., Quality control of commercial quillaja (Quillaja saponaria Molina) extracts by reverse phase HPLC. J. Sci. Food Agr. 2000, 80, 2063-2068. 67. San Martín, R.; Briones, R., Industrial uses and sustainable supply of Quillaja saponaria (Rosaceae) saponins. Econ. Bot. 1999, 53, 302-311. 68. Wang, P.; Kim, Y. J.; Navarro-Villalobos, M.; Rohde, B. D.; Gin, D. Y., Synthesis of the potent immunostimulatory adjuvant QS-21A. J. Am. Chem. Soc. 2005, 127, 3256-3257. 69. Kim, Y. J.; Wang, P.; Navarro-Villalobos, M.; Rohde, B. D.; Derryberry, J.; Gin, D. Y., Synthetic studies of complex immunostimulants from Quillaja saponaria: synthesis of the potent clinical immunoadjuvant QS-21Aapi. J. Am. Chem. Soc. 2006, 128, 11906-11915. 70. Deng, K.; Adams, M. M.; Damani, P.; Livingston, P. O.; Ragupathi, G.; Gin, D. Y., Synthesis of QS-21-xylose: establishment of the immunopotentiating activity of synthetic QS-21 adjuvant with a melanoma vaccine. Angew Chem. Int. Ed. Engl. 2008, 47, 6395-6398. 71. Marciani, D. J.; Reynolds, R. C.; Pathak, A. K.; Finley-Woodman, K.; May, R. D., Fractionation, structural studies, and immunological characterization of the semi-synthetic Quillaja saponins derivative GPI-0100. Vaccine 2003, 21, 3961-3971. 72. Marciani, D. J.; Press, J. B.; Reynolds, R. C.; Pathak, A. K.; Pathak, V.; Gundy, L. E.; Farmer, J. T.; Koratich, M. S.; May, R. D., Development of semisynthetic triterpenoid saponin derivatives with immune stimulating activity. Vaccine 2000, 18, 3141-3151. 73. Ragupathi, G.; Gardner, J. R.; Livingston, P. O.; Gin, D. Y., Natural and synthetic saponin adjuvant QS-21 for vaccines against cancer. Expert Rev. Vaccines 2011, 10, 463-470. 74. Liu, G.; Anderson, C.; Scaltreto, H.; Barbon, J.; Kensil, C. R., QS-21 structure/function studies: effect of acylation on adjuvant activity. Vaccine 2002, 20, 2808-2815. 75. Wang, P.; Devalankar, D. A.; Dai, Q.; Zhang, P.; Michalek, S. M., Synthesis and evaluation of QS-21-based immunoadjuvants with a terminal-functionalized side chain incorporated in the west wing trisaccharide. J. Org. Chem. 2016, 81, 9560-9566. 76. Wang, P.; Dai, Q.; Thogaripally, P.; Zhang, P.; Michalek, S. M., Synthesis of QS-21-based immunoadjuvants. J. Org. Chem. 2013, 78, 11525-11534. 77. Gin, D. Y.; Adams, M.; Deng, K.; Perl, N.; Won, A.; Livingston, P.; Ragupathi, G., Triterpene saponins, methods of synthesis, and uses thereof. Google Patents: 2014. 78. Konishi, N.; Shirahata, T.; Yokoyama, M.; Katsumi, T.; Ito, Y.; Hirata, N.; Nishino, T.; Makino, K.; Sato, N.; Nagai, T.; Kiyohara, H.; Yamada, H.; Kaji, E.; Kobayashi, Y., Synthesis of bisdesmosidic oleanolic acid saponins via a glycosylation-deprotection sequence under continuous microfluidic/batch conditions. J. Org. Chem. 2017, 82, 6703-6719. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78767 | - |
| dc.description.abstract | 皂皮樹（Quillaja saponaria）是一種富含皂苷的常綠樹。其樹皮的提取物已被廣泛研究並證明具有良好的佐劑活性。將其粗樹皮提取物在溫和的鹼性條件下水解化學不穩定的醯基側鏈，並以醯胺鍵與脂族十二烷基鏈連接，可以得到半合成的GPI-0100。與QS-21相比，它是一種更安全的佐劑，然而，其富含異質成分和潛在的毒性阻礙了其在臨床中的廣泛應用。由於在合成這種皂苷時，將葡萄醣醛酸基與皂皮酸C-3的鍵結是困難及有挑戰性的。為了解決這個問題，我們提出了兩種策略。首先，我們利用6-N-葡萄醣醛基取代葡萄醣醛酸基來合成GPI-0100的葡糖苷酸類源物。在室溫TBDMSOTf酸催化下，6-N-葡萄醣醛基與皂皮酸C-3位置的醣基化可以達到71%的產率。然後將N-6'位置的疊氮還原，並以Cbz保護基做保護，除去C-28的烯丙基後得到化合物39。去保護後的羧基與三醣進行醣基化得到88% 產率（α/β 比例 = 1/10）的40。在40個別與不同芳香基烷基酸鍵結後，進行去保護得到產物42a和42b。另外，我們也開發了一種能夠從皂皮樹皮提取物中以38％分離產率分離出在C-3含有三醣的皂皮酸皂苷44。接著以半合成的方式在C-28的羧基接上三醣，以BF3•OEt2為活化劑得到87%含有六醣的皂苷化合物。在全部去保護後，與末端含有芳香環的烷基胺以醯胺鍵做鍵結，得到最終產物51a和51b。這兩系列的化合物將會進一步評估其免疫刺激能力。 | zh_TW |
| dc.description.abstract | Quillaja saponaria is an evergreen tree and rich in quillaic acid containing saponins. Extracts from its bark have been extensively studied and demonstrated as promising adjuvant activity. The crude bark extract was processed under mild basic hydrolysis and then conjugated with an aliphatic dodeacyl chain via a hydrolytically stable amide bond to give GPI-0100. Comparing to QS-21, it is a safer adjuvant. However, its heterogeneous composition and inherent toxicity prevent its wider use in clinic. These saponins bearing a glucuronyl group at C-3 position of quillaic acid made it difficult in synthesis process. To solve this problem, two strategies were conducted. Firstly, we synthesized the glucuronide congeners of GPI-0100 via replacing glucurosyl group by 6-N-glycosyl group. Using TBDMSOTf as a promotor, the glycosylation of 6-N-glycosyl donor with quillaic acid 3 gave 36 in 71% yield. Followed by azide reduction and Cbz formation at N-6′ position, and then removal of the allyl group at C-28 afforded compound 39. 39 was glycosylated with trisaccharide donor to afford 40 in 88% yield (/β ratio = 1/10). Compound 40 was then subjected to hydrogenolysis under 55 psi H2 catalyzed by 10% Pd(OH)2/C, followed by amide formation with two arylalkanoic acids, acid/base hydrolysis to afford final products 42a and 42b. Secondly, we developed an isolation method from Q. saponaria tree bark extract to get 3-O-trisaccharide containing quillaic acid 44 in 38% isolated yield, 44 was also semi-synthesized with trisachharide at C-28 position by using BF3•OEt2 as a promotor to afford 46 (87% yield), followed by global deprotections and then conjugated with two arylalkyl amines to give finals 51a and 51b. Both series of compounds will be evaluated for immunostimuating ability in the future. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T15:17:55Z (GMT). No. of bitstreams: 1 ntu-108-R06423030-1.pdf: 27416181 bytes, checksum: 01ad35a42c46dfdbf94612312481dc25 (MD5) Previous issue date: 2019 | en |
| dc.description.tableofcontents | 誌謝 i
中文摘要 ii Abstract iii Abbreviations v 1. Introduction 1 1.1. Quillaja saponaria 1 1.1.1. Phytochemicals from Quillaja saponaria 2 1.1.2. Biological activity 3 1.1.3. Quillaic acid 4 1.1.4. Production of Q. Saponaria saponins 5 1.1.5. Quil-A® 6 1.1.6. QS-21 and its purified analogues 7 1.2. Vaccine adjuvant 11 1.2.1. Approved vaccine adjuvants 12 1.2.2. QS-21 adjuvanted vaccine 13 1.2.3. Plausible mechanism of QS-21 15 1.3. Development of QS-21 16 1.3.1. Challenges of using QS-21 16 1.3.2. Synthesis of QS-21 17 1.3.3. GPI-0100 18 1.3.4. Synthesis of QS-21 analogues inspired by GPI-0100 19 1.3.5. Truncation of glucuronide and 28-O-linked tetrasaccharide 21 1.3.6. Development of GPI-0100 analogues in our lab 23 2. Motivation 24 3. Results and discussion 26 3.1． Retrosynthetic analysis 26 3.2． Part 1: Synthesis of building blocks and trisaccharide 27 3.3． Part 2: Synthesis of azido-glucose donor 29 3.4． 3-O-Glycosylation of Quillaic ester 31 3.5． Synthesis of tetrasaccharide saponin 31 3.6． Part 3: Semisynthesis of hexasaccharide saponins 35 3.7． Global deprotection and amide formation of hexasaccharide saponins 37 4. Conclusion 41 5. Experimental section 43 5.1. General Procedures 43 5.2. Chemical reagents 43 5.3. Instruments 45 5.4. Synthetic Procedures 46 6. References 84 Appendixes 97 | |
| dc.language.iso | en | |
| dc.subject | QS-21 | zh_TW |
| dc.subject | 疫苗佐劑 | zh_TW |
| dc.subject | 皂? | zh_TW |
| dc.subject | GPI-0100 | zh_TW |
| dc.subject | QS-21 | en |
| dc.subject | Vaccine adjuvant | en |
| dc.subject | GPI-0100 | en |
| dc.subject | Saponins | en |
| dc.title | 半合成GPI-0100衍生物暨合成其葡萄醣醛酸類源物作為免疫活化劑 | zh_TW |
| dc.title | Semisynthesis of GPI-0100 Analogues and Synthesis of Its Glucuronide-Congeners as Immunostimulators | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 107-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 李水盛,張嘉銓,忻凌偉 | |
| dc.subject.keyword | 疫苗佐劑,皂?,QS-21,GPI-0100, | zh_TW |
| dc.subject.keyword | Vaccine adjuvant,Saponins,QS-21,,GPI-0100, | en |
| dc.relation.page | 157 | |
| dc.identifier.doi | 10.6342/NTU201901596 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2019-07-18 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥學研究所 | zh_TW |
| Appears in Collections: | 藥學系 | |
Files in This Item:
| File | Size | Format | |
|---|---|---|---|
| ntu-108-R06423030-1.pdf Restricted Access | 26.77 MB | Adobe PDF |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.