請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/23231完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 梁碧惠 | |
| dc.contributor.author | Ying-Hsin Wang | en |
| dc.contributor.author | 王英馨 | zh_TW |
| dc.date.accessioned | 2021-06-08T04:48:46Z | - |
| dc.date.copyright | 2011-10-07 | |
| dc.date.issued | 2011 | |
| dc.date.submitted | 2011-08-15 | |
| dc.identifier.citation | 1.Mahato, S. B.; Ganguly, A. N.; Sahu, N. P. Steroid saponins. Phytochemistry 1982, 21, 959-78.
2.Tschesche, R.; Wulff, G. Chemistry and biology of saponins. Fortschr. Chem. Org. Naturst. 1973, 30, 461-606. 3.Sparg, S. G.; Light, M. E.; Staden, J. V. Biological activities and distribution of plant saponins. J. Ethnopharmacol. 2004, 94, 219-243. 4.Yu, B.; Zhang, Y.; Tang, P. Carbohydrate chemistry in the total synthesis of saponins. Eur. J. Org. Chem. 2007, 2007, 5145-5161. 5.Hufford, C. D.; Liu, S.; Clark M. A. Antifungal activity of trillinm grandiflorum constituents. J. Nat. Prod. 1988, 51, 94-98. 6.Li, B.; Yu, B.; Hui, Y.; Li, M.; Han, X.; Fung, K. P. An improved synthesis of the saponin, polyphyllin D. Carbohydr. Res. 2001, 331, 1-7. 7.Takechi, M.; Tanaka, Y. Structure-activity relationships of synthetic diosgenyl monoglycosides. Phytochemistry, 1991, 30, 2557-2558. 8.Pettit, G. R.; Doubek, D. L.; Herald, D. L. Isolation and structure of cytostatic steroidal saponins from the african medicinal plant balanites aegyptica. J. Nat. Prod. 1991, 54, 1491-1502. 9.Modjtahedi, H.; Dean, C. The binding of HB-EGF to tumor cells is blocked by mAbs which act as EGF and TGFα antagonists. Biochem. Biophys. Res. Commun. 1995, 207, 389-397. 10.Ma, X.; Yu, B.; Hui, Y.; Xiao, D.; Ding, J. Synthesis of glycosides bearing the disaccharide of OSW-1 or its 1→4-linked analogue and their antitumor activities. Carbohydr. Res. 2000, 329, 495-505. 11.Zhanga, Y.; Li, H. Z.; Zhanga, Y. J.; Jacobb, M. R.; Khanb, S. I.; Li, X. C.; Yang, C. R. Atropurosides A-G, new steroidal saponins from Smilacina atropurpurea. Steroids 2006, 71, 712-719. 12.Fernández-Herrera, M. A.; Mohan, S.; López-Muñoz, H.; Hernández-Vázquez, J. M. V.; Pérez-Cervantes, E.; Escobar-Sánchez, M. L.; Sánchez-Sánchez, L.; Regla, I.; Pinto, B. M.; Sandoval-Ramírez, J. Synthesis of the steroidal glycoside (25R)-3β,16β-diacetoxy-12,22-dioxo-5α-cholestan- 26-yl β-D-glucopyranoside and its anti-cancer properties on cervicouterine HeLa, CaSki, and ViBo cells. Eur. J. Med. Chem. 2010, 45, 4827-4837. 13.Honda, I. J. Arch. exp. Pharm. Path. 1904, 51, 221. 14.Madaeva, O. S.; Ryzhkova, V. K.; Panina, V. V. Saponins of Dioscorea polystachya XIV. Dioscinin. Chem. Nat. Compd. 1967, 3, 128-130. 15.Moalic, S.; Liagre, B.; Corbiere, C.; Bianchi, A.; Dauca, M.; Bordji, K.; Beneytout, J. L. A plant steroid, diosgenin, induces apoptosis, cell cycle arrest and COX activity in osteosarcoma cells. FEBS Lett. 2001, 506, 225-230. 16.Kaskiw, M. J.; Tassotto, M. L.; Moka, M.; Tokar, S. L.; Pycko, R.; Th’ng, J.; Jiang, Z. H. Structural analogues of diosgenyl saponins: synthesis and anticancer activity. Bioorg. Med. Chem. 2009, 17, 7670-7679. 17.Kaskiw, M. J.; Tassotto, M. L.; Th’ng, J.; Jiang, Z. H. Synthesis and cytotoxic activity of diosgenyl saponin analogues. Bioorg. Med. Chem. 2008, 16, 3209-3217. 18.Mana, S.; Gao, W.; Zhang, Y.; Huang, L.; Liu, C. Chemical study and medical application of saponins as anti-cancer agents. Fitoterapia 2010, 81, 703-714. 19.Takechi, M.; Shimada, S.; Tanaka, Y. Structure-activity relationships of the saponins dioscin and dioscinin. Phytochemistry 1991, 30, 3943-3944. 20.Wang, Z.; Zhou, J. B.; Ju, Y.; Zhang, H.; Liu, M.; Li, X. Effects of two saponins extracted from the Polygonatum Zanlanscianense pamp on the human leukemia (HL-60) cells. Biol. Pharm. Bull. 2001, 24, 159-162. 21.Hengartner, M. O. The biochemistry of apoptosis. Nature 2000, 407, 770-776. 22.Cai, J.; Liu, M.; Wang, Z.; Ju, Y. Apoptosis induced by dioscin in Hela cells. Biol. Pharm. Bull. 2002, 25, 193-196. 23.Liu, M. J.; Wang, Z.; J, Y.; Zhou, J. B.; Wang, Y.; Wong, R. N. S. The mitotic-arresting and apoptosis-inducing effects of diosgenyl saponins on human leukemia cell lines. Biol. Pharm. Bull. 2004, 27, 1059-1065. 24.Lin, F.; Wang, R. Hemolytic mechanism of dioscin proposed by molecular dynamics simulations. J. Mol. Model. 2010, 16, 107-118. 25.Huo, R.; Zhou, Q.; Wang, B. X.; Tashiro, S. I.; Onosera, S.; Ikejima, T. Diosgenin induces apoptosis in HeLa cells via activation of caspase pathway. Acta Pharmacol Sin 2004, 8, 1077-1082. 26.Wang, Y.; Cheung, Y. H.; Yang, Z.; Chiu, J. F.; Che, C. M.; He, Q. Y. Proteomic approach to study the cytotoxicity of dioscin (saponin). Proteomics 2006, 6, 2422-2432. 27.Miyashita, H.; Ikeda, T.; Nohara, T. Synthesis of neosaponins and neoglycolipids containing a chacotriosyl moiety. Carbohydr. Res. 2007, 342, 2182-2191. 28.Wang, Y.; Zhang, Y.; Zhu, Z., Zhu, S.; Li, Y.; Li, M.; Yu, B. Exploration of the correlation between the structure, hemolytic activity, and cytotoxicity of steroid saponins. Bioorg. Med. Chem. 2007, 15, 2528-2532. 29.Mimaki, Y.; Yokosuka, A.; Kuroda, M.; Sashida, Y. Cytotoxic activities and structure–cytotoxic relationships of steroidal saponins. Biol. Pharm. Bull. 2001, 24, 1286-1289. 30.Li, M.; Han, X.; Yu, B. Synthesis of monomethylated dioscin derivatives and their antitumor activities. Carbohydr. Res. 2003, 338, 117-121. 31.Zhu, S.; Zhang, Y.; Li, M.; Yu, J.; Zhang, L.; Li, Y.; Yu, B. Synthesis and cytotoxicities of dioscin derivatives with decorated chacotriosyl residues. Bioorg. Med. Chem. Lett. 2006, 16, 5629-5632. 32.Li, W.; Qiu, Z.; Wang, Y.; Zhang, Y.; Li, M.; Yu, J.; Zhang, L.; Zhu, Z.; Yu, B. Synthesis, cytotoxicity, and hemolytic activity of 6′-O-substituted dioscin derivatives. Carbohydr. Res. 2007, 342, 2705-2715. 33.Hernández, J. C.; León, F.; Brouard, I.; Torres, F.; Rubio, S.; Quintana, J.; Estévez, F.; Bermejo, J. Synthesis of novel spirostanic saponins and their cytotoxic activity. Bioorg. Med. Chem. 2008, 16, 2063-2076. 34.Kim, J. H.; Yang, H.; Park, J.; Boons, G. J. A general strategy for stereoselective glycosylations. J. Am. Chem. Soc. 2005, 127, 12090-12097. 35.Deng, S.; Yu, B.; Hui, Y. A facile synthetic approach to a group of structurally typical diosgenyl saponins. Tetrahedron Lett. 1998, 39, 6511-6514. 36.Li, C.; Yu, B.; Liu, M.; Hui, Y. Synthesis of diosgenyl α-L-rhamnopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→3)]-β-D-glucopyranoside (gracillin) and related saponins. Carbohydr. Res. 1998, 306, 189-195. 37.Jiang, L.; Chan, T. H. Regioselective acylation of hexopyranosides with pivaloyl chloride. J. Org. Chem. 1998, 63, 6035-6038. 38.Li, B.; Yu, B.; Hui, Y.; Li, M.; Han, X.; Fung, K. P. An improved synthesis of the saponin, polyphyllin D. Carbohydr. Res. 2001, 331, 1-7. 39.Yu, B.; Tao, H. Glycosyl trifluoroacetimidates. Part 1: Preparation and application as new glycosyl donors. Tetrahedron Lett. 2001, 42, 2405-2407. 40.Yu, B.; Tao, H. Glycosyl trifluoroacetimidates. 2. Synthesis of dioscin and xiebai saponin I. J. Org. Chem. 2002, 67, 9099-9102. 41.Du, Y.; Gu, G.; Wei, G.; Hua, Y.; Linhardt, R. J. Synthesis of saponins using partially protected glycosyl donors. Org. Lett. 2003, 5, 3627-3630. 42.Ikeda, T.; Miyashita, H.; Kajimoto, T.; Nohara, T. Synthesis of neosaponins having an α-L-rhamnopyranosyl-(1→4)-[α-L-rhamnopyranosyl-(1→ 2) ]-D-glucopyranosyl glyco-linkage. Tetrahedron Lett. 2001, 42, 2353-2356. 43.Miyashita, H.; Kai, Y.; Noharab, T.; Ikeda, T. Efficient synthesis of α- and β-chacotriosyl glycosides using appropriate donors, and their cytotoxic activity. Carbohydr. Res. 2008, 343, 1309-1315. 44.Randolph, J. T.; Danishefsky, S. J. First synthesis of a digitalis saponin. Demonstration of the scope and limitations of a convergent scheme for branched oligosaccharide synthesis by the logic of glycal assembly. J. Am. Soc. 1995, 117, 5693-5700. 45.Dong, H.; Pei, Z.; Byström, S.; Ramström, O. Reagent-dependent regioselective control in multiple carbohydrate esterifications. J. Org. Chem. 2007, 72, 1499-1502. 46.Bouzide, A.; Sauve, G. Highly selective silver(l) oxide mediated monoprotection of symmetrical diols. Tetrahedron Lett. 1997, 38, 5945-5948. 47.Bouzide, A.; Sauve, G. Silver(I) Oxide mediated highly selective monotosylation of symmetrical diols. Application to the synthesis of polysubstituted cyclic ethers. Org. Lett. 2002, 4, 2329-2332. 48.Wang, H.; She, J.; Zhang, L. H.; Ye, X. S. Silver(I) oxide mediated selective monoprotection of diols in pyranosides. J. Org. Chem. 2004, 69, 5774-5777. 49.Iversen, T.; Bundle, D. R. Benzyl trichloroacetimidate, a versatile reagent for acid-catalysed benzylation of hydroxy-groups. J. Chem. Soc. Chem. Commun. 1981, 1240-1241. 50.Huang, L.; Huang, X. Highly Efficient syntheses of hyaluronic acid oligosaccharides. Chem. Eur. J. 2007, 13, 529-540. 51.Debenham, D. D.; Toone, E. J. Regioselective reduction of 4,6-O-benzylidenes using triethylsilane and BF3•Et2O. Tetrahedron: Asymmetry 2000, 11, 385-387. 52.Hassner, A.; Strand, G.; Rubinstein, M.; Patchornik, A. Levulinic esters. Alcohol protecting group applicable to some nucleosides. J. Am. Chem. Soc. 1975, 97, 1614-1615. 53.Calinaud, P.; Gelas, J. Synthesis of isopropylidene, benzylidene, and related acetals. Preparative Carbohydrate Chemistry New York, 1997, 3-33. 54.Saito, A.; Wakao, M.; Deguchi, H.; Mawatari, A.; Sobel, M.; Suda, Y. Towards the assembly of heparin and heparan sulfate oligosaccharide libraries: efficient synthesis of uronic acid and disaccharide building blocks. Tetrahedron, 2010, 66, 3951-3962. 55.Zemple´n, G.; Pacsu, E. Ber. Dtsch. Chem. Ges. 1929, 62, 1613-1614. 56.Daragics, K.; Fu¨gedi, P. (2-Nitrophenyl)acetyl: a new, selectively removable hydroxyl protecting group. Org. Lett. 2010, 12, 2076-2079. 57.Johnsson, R.; Ohlin, M.; Ellervik, U. Reductive openings of benzylidene acetals revisited: a mechanistic scheme for regio- and stereoselectivity J. Org. Chem. 2010, 75, 8003–8011. 58.Zhu, T.; Boons, G. J. A new set of orthogonal-protecting groups for oligosaccharide synthesis on a polymeric support. Tetrahedron: Asymmetry 2000, 11, 199-205. 59.Zhang, Y.; Li, Y.; Guo, T.; Guan, H.; Shi, J.; Yu, Q.; Yu, B. Syntheses of chlorogenin 6α-O-acyl-3-O-β-chacotriosides and their antitumor activities. Carbohydr. Res. 2005, 340, 1453-1459. 60.Jiang, B.; Shi, H. P.; Tian, W. S.; Zhou, W. S. The convergent synthesis of novel cytotoxic certonardosterol D2 from diosgenin. Tetrahedron 2008, 64, 469-476. 61.Tatai, J.; Fugedi, P. A new, powerful glycosylation method: Activation of thioglycosides with dimethyl disulfide-triflic anhydride. Org. Lett. 2007, 9, 4647-4650. 62.Nguyen, H. M.; Chen, Y.; Duron, S. G.; Gin, D. Y. Sulfide-mediated dehydrative glycosylation. J. Am. Chem. Soc. 2001, 123, 8766-8772. 63.Schmidt, R. R.; Kinzy, W. Anomeric-oxygen activation for glycoside synthesis: the trichloroacetimidate method. Adv. Carbohydr. Chem. Biochem. 1994, 50, 21-123. 64.Jeker, N.; Tamm, C. Synthesis of new, unnatural macrocyclic trichothecenes: 3-isoverrucarin A (( 1'-O)(3→4)abeo-verrucarin A), verrucinol, and verrucene. Helv. Chim. Acta. 1988, 71, 1895-1903. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/23231 | - |
| dc.description.abstract | 皂素為天然存在之配醣體，具有相當多元化之結構以及生物活性，其結構上主要分成三萜類和類固醇類兩大類。類固醇類皂素通常具有紅血球細胞溶血作用及抑制腫瘤生長的活性，其活性需要醣基部份之結構，但是其醣基在分子層面的角色仍未明。皂素由於結構上的複雜和純物質取得不易，發展一個實際可行的方法進一步針對醣基部分的修飾將可對皂素結構與活性的關係進一步了解，將有機會發現新的治療物質。
Dioscin (diosgeninyl 3b-O-(2,4-di-O-a-L-rhamnopyranosyl)-b-D-glucoside)屬於固醇類之spirostan皂素，為最常見於薯蕷科植物塊莖的一種皂素，具有抗癌活性。為了探討結構與活性的關係，我們設計和用保護基策略合成一系列的衍生物，以葡萄糖為dioscin的結構核心，並利用位向選擇保護策略得到3,6-di-O-benzyl-4-O-levulinoyl-2-O-((2-nitro)phenylacetyl)-D-glucopyranosyl trichloroacetimidate (141)，與6a-O-acteyl-chlorogenin (145)醣化後獲得化合物 164，之後藉由選擇性去保護、與不同的醣基提供者醣化和全面的去保護得到dioscin分子資料庫。 在生物活性探討方面，我們利用細胞存活率測定其對前列腺癌細胞PC-3造成之影響，結果顯示給予10 uM劑量，所有化合物對於PC-3細胞株皆無生長抑制作用，而2'-OH接上L-fucosyl (97)或L-rhamnosyl (104)為此一系列衍生物中具有最佳之活性，但其GI50皆大於30 uM，整體而言，此dioscin衍生物對於前列腺癌細胞並無抗癌活性，未來將會針對其他癌細胞株進行測試。 | zh_TW |
| dc.description.abstract | Saponin, a naturally occurring glycoside with diversities of structures and bioactivities, can be structurally divided into 2 major types-triterpenoidal and steroidal glycosides. The common features of steroidal spirostan saponins are hemolytic and cytotoxic where the sugar units are often required for function in vivo, but their roles at the molecular level are not well-understood. Due to the complexity of structures and limited availability of homogeneous saponins, development of practical methods for modification of the carbohydrate domain of natural products may lead to a better understanding of the structure activity relationships (SAR) of saponins and have better chance to identify new therapeutics.
Dioscin (diosgeninyl 3b-O-(2,4-di-O-a-L-rhamnopyranosyl-b-D-glucoside)), one of the most common steroidal spirostane saponins found in rhizome of Dioscoreaceae, exhibits potent antitumor activities. Thus, in order to study the SAR of dioscin, a series of analogues were designed and synthesized by the protection strategy. Glucose, as a common core structure of dioscin, was chosen and orthogonal protected to 3,6-di-O-benzyl-4-O-levulinoyl-2-O-(2-nitrophenylacetyl)-D-glucopyranosyl trichloroacetimidate 141. Compound 141 was then subjected to glycosylate with 6b-O-acteyl-chlorogenin 145 to give compound 164 which was selectively deprotected, glycosylated with various glycosyl donors, and global deprotected to obtain a library of dioscin analogues. The effect of these analogues on human prostate carcinoma (PC-3) was studied via SRB assay, and the results showed that the compound had no inhibition of growth at 10 uM level. Only 97 and 104 with 2'-O- L-fucosyl and L-rhamnosyl, respectively, displayed weak cytotoxicities at a dose of 30 uM (still with GI50 ＞30 uM). Current study demonstrated that these dioscin analogues were not cytotoxic toward PC-3. Further studies of these derivatives for other cancer cell lines will be performed. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T04:48:46Z (GMT). No. of bitstreams: 1 ntu-100-R98423024-1.pdf: 53034075 bytes, checksum: 9f5b19db4d6bafa7c3d321125dee5db2 (MD5) Previous issue date: 2011 | en |
| dc.description.tableofcontents | 目錄
中文摘要 Ⅰ 英文摘要 Ⅱ 圖目錄 Ⅴ 路徑目錄 Ⅵ 表目錄 Ⅶ 詞彙 Ⅷ 一、研究背景 1 1.1.皂素 (Saponin)之簡介 1 1.2.Dioscin 2 1.3.Dioscin的作用機制 3 1.4.Dioscin類似物之活性結構關係 4 1.4.1.Sapogenin部分的研究 4 1.4.2.醣基部分的研究 7 1.4.3.Dioscin及其類似物之合成方法 12 1.4.3.1.線性合成方法 14 1.4.3.2.聚合性合成方法 18 1.5.研究動機與目的 21 二、結果與討論 23 2.1.Dioscin類似物合成策略 23 2.1.1.D-Glucose之保護基合成策略 24 2.1.2.Chlorogenin的合成 31 2.1.3.Glycosyl trichloroacetimidate供給者之合成 32 2.1.4.核心結構及類似物的合成 35 2.1.5.化合物108結構的確定 42 2.2.生物活性 43 三、結論 46 四、實驗部分 47 4.1.實驗試劑及儀器來源 47 4.2.合成步驟及數據分析 50 五、參考文獻 130 六、附圖 137 | |
| dc.language.iso | zh-TW | |
| dc.title | 利用位向選擇保護策略合成Dioscin類似物作為有潛力之抗癌藥物 | zh_TW |
| dc.title | Synthesis of Dioscin Analogues as Potential Anticancer Agents by Orthogonal Protection Strategy | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 99-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 李水盛,顧記華,忻凌偉,劉景平 | |
| dc.subject.keyword | 皂素,dioscin,抗癌,保護基,位向選擇, | zh_TW |
| dc.subject.keyword | saponin,dioscin,anticancer,protection,orthogonal, | en |
| dc.relation.page | 250 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2011-08-16 | |
| 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-100-1.pdf 目前未授權公開取用 | 51.79 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。