進階搜尋


  查詢北醫館藏
系統識別號 U0007-0107201101530400
論文名稱(中文) 合成6-6雜環類緣物作為新穎組蛋白去乙醯酶抑制劑的研究
論文名稱(英文) Synthesis of [6, 6]-Heterocycles Analogs as A Novel Class of Potent Histone Deacetylase Inhibitors
校院名稱 臺北醫學大學
系所名稱(中) 藥學研究所
系所名稱(英) Graduate Institute of Pharmacy
學年度 99
學期 2
出版年 100
研究生(中文) 劉宜旻
研究生(英文) Yi-Min Liu
學號 M301098022
學位類別 碩士
語文別 中文
口試日期 2011-06-21
論文頁數 278頁
口試委員 指導教授-劉景平
委員-陳繼明
委員-李慶國
中文關鍵字 組蛋白去乙醯酶  抑制劑 
英文關鍵字 組蛋白去乙醯酶  抑制劑 
學科別分類
中文摘要 組蛋白去乙醯酶 (histone deacetylase, HDAC)與癌細胞生長非常相關,不止對於癌症也可對其他疾病作為治療標靶,且美國FDA (Food and Drug Administration)於2006年通過第一個組蛋白去乙醯酶抑制劑 (histone deacetylase inhibitor, HDACi),即SAHA (Vorinostat, Zolinza○R),用於治療皮膚T細胞淋巴癌 (cutaneous T-cell lymphoma, CTCL),並緊接著在2009年年底通過第二個HDACi,同樣是用於治療CTCL的FK228 (Romidepsin, Istodax○R)。現今尚有許多HDACi正在進行臨床實驗,此類藥物也因而成為了研發重點的抗癌藥物之一。
HDACi大多數是從天然物中萃取純化而得或是由化學合成取得。基本上,HDACi依據結構可大致分為六類:分別為短鏈脂肪酸、hydroxamic acids、環狀胜肽、benzamides、親電性酮類以及其它。
本實驗室參考了目前已上市或仍在進行臨床試驗的HDAC inhibitors,發現N-hydroxyacrylamide及benzamide的官能基,是抑制活性的主要來源;另外,在觀察其他抗癌的小分子化合物中,含氮之雜環常作為core structure。是故,本實驗室決定探討含氮之[6,6]雜環作為主要的骨架,同時在其N位上以各種不同的苯 磺胺類及非苯磺胺類作取代,且在基本骨架上導入N-hydroxyacrylamide或benzamide官能基;同時,對於苯磺胺類的取代基以及連結上述兩個官能基的碳鏈作修飾,合成兩系列化合物,以了解HDAC抑制活性與結構之間的關係。
此次合成出之目標化合物中,以具有4’-甲氧基取代的苯磺胺類及官能基團為N-hydroxyacrylamide的化合物為最具抗癌活性。另一方面,將苯磺胺類的取代基改為鹵素原子或拉電子基基團,其抗癌活性皆下降;此外,官能基團為benzamide的目標化合物,其抗癌活性表現也為下降。此實驗日後仍會於本實驗室進行進一步的結構修飾,以期能合成出最具抗癌活性的目標化合物。
英文摘要 Histone deacetylase (HDAC) is related to the growth of cancer cell extremely. Not only used in cancer, it can be used a therapeutic target also in other diseases. The U. S. Food and Drug Administraction (FDA) approved the first histone deacetylase inhibitor (HDACi), SAHA (Vorinostat, Zolinza○R), used in the treatment of cutaneous T-cell lymphoma (CTCL) in 2006. Soon, FDA approved the second HDACi, FK228 (Romidepsin, Istodax○R), also used in the treatment of CTCL in the end of the 2009. There are still many HDACs undergoing the clinical trials, the compounds of this class have become the one of the research points of the anti-cancer drugs.
HDACi is taken from the nature via extraction and purification and chemical synthesized. Basically, according to the structures, the HDACi can separate to six class, they are short-chain fatty acid, hydroxamic acids, cyclic peptides, benzamides, electrophilic ketones and others.
After we compare the approved drugs and undergoing clinical trials compounds, we discover that the functional group of N-hydroxyacrylamide and benzamide is the source of inhibitory activity. Besides, the nitrogen-containing heterocycle is usually used as the core structure in other small molecular compounds of anti-cancer agents. Therefore, we decided to discover the nitrogen-containing [6, 6]-heterocycle as the core structure, and meanwhile, replace the substituted-phenyl sulfonamide and non-substituted-phenyl sulfonamide at N position. Also, introduce the functional group of N-hydroxyacrylamide or benzamide to the core structure. Furthermore, modify the carbon chain which connected the substituted groups and functional groups to synthesize two series compound to understand the relationship between inhibitory activity and the structure.
In this experiment, the target compound which possesses the substitution group of 4’methoxy benzenesulfonamide and functional group of N-hydroxyacrylamide shows the best anti-tumor activity. On the other hand, changing the 4’methoxy group to the halogens or the nitro group shows the lower anti-tumor activity; others like changing the N-hydroxyacrylamide group to the banzamide group also shows the lower anti-tumor activity. Our lab will continue to modify the structure of the compounds of this experiment and try to synthesize the most potent compound as HDAC inhibitor.
論文目次 目錄……………………………………………………………………………………………… I
附表目錄……………………………………………………………………………………… V
附圖目錄……………………………………………………………………………………… VI
附流程目錄…………………………………………………………………………………… VIII
摘要……………………………………………………………………………………………… IX
英文摘要……………………………………………………………………………………… X
壹、緒論 ……………………………………………………………………………………… 001
貳、實驗目的與設計……………………………………………………………………… 036
參、化學合成………………………………………………………………………………… 039
肆、藥理活性研究與討論……………………………………………………………… 045
伍、實驗部份………………………………………………………………………………… 050
陸、化合物合成步驟……………………………………………………………………… 053
化合物31之合成步驟 053
化合物32之合成步驟 054
化合物33a之合成步驟 055
化合物34a之合成步驟 056
化合物35a之合成步驟 057
化合物36a之合成步驟 058
化合物37a之合成步驟 059
化合物27a之合成步驟 060
化合物33b之合成步驟 061
化合物34b之合成步驟 062
化合物35b之合成步驟 063
化合物36b之合成步驟 064
化合物37b之合成步驟 065
化合物27b之合成步驟 066
化合物33c之合成步驟 067
化合物34c之合成步驟 068
化合物35c之合成步驟 069
化合物36c之合成步驟 070
化合物37c之合成步驟 071
化合物27c之合成步驟 072
化合物33d之合成步驟 073
化合物34d之合成步驟 074
化合物35d之合成步驟 075
化合物36d之合成步驟 076
化合物37d之合成步驟 077
化合物27d之合成步驟 078
化合物33e之合成步驟 079
化合物34e之合成步驟 080
化合物35e之合成步驟 081
化合物36e之合成步驟 082
化合物37e之合成步驟 083
化合物27e之合成步驟 084
化合物33f之合成步驟 085
化合物34f之合成步驟 086
化合物35f之合成步驟 087
化合物36f之合成步驟 088
化合物37f之合成步驟 089
化合物27f之合成步驟 090
化合物33g之合成步驟 091
化合物34g之合成步驟 092
化合物35g之合成步驟 093
化合物36g之合成步驟 094
化合物37g之合成步驟 095
化合物27g之合成步驟 096
化合物33h之合成步驟 097
化合物34h之合成步驟 098
化合物35h之合成步驟 099
化合物36h之合成步驟 100
化合物37h之合成步驟 101
化合物27h之合成步驟 102
化合物33i之合成步驟 103
化合物34i之合成步驟 104
化合物35i之合成步驟 105
化合物36i之合成步驟 106
化合物37i之合成步驟 107
化合物27i之合成步驟 108
化合物33j之合成步驟 109
化合物34j之合成步驟 110
化合物35j之合成步驟 111
化合物36j之合成步驟 112
化合物37j之合成步驟 113
化合物27j之合成步驟 114
化合物33k之合成步驟 115
化合物34k之合成步驟 116
化合物35k之合成步驟 117
化合物36k之合成步驟 118
化合物37k之合成步驟 119
化合物27k之合成步驟 120
化合物43g之合成步驟 121
化合物44g之合成步驟 122
化合物45g之合成步驟 123
化合物27l之合成步驟 124
化合物43h之合成步驟 125
化合物44h之合成步驟 126
化合物45h之合成步驟 127
化合物27m之合成步驟 128
化合物38a之合成步驟 129
化合物39a之合成步驟 130
化合物40a之合成步驟 131
化合物41a之合成步驟 132
化合物42a之合成步驟 133
化合物28a之合成步驟 134
化合物38b之合成步驟 135
化合物39b之合成步驟 136
化合物40b之合成步驟 137
化合物41b之合成步驟 138
化合物42b之合成步驟 139
化合物28b之合成步驟 140
化合物38c之合成步驟 141
化合物39c之合成步驟 142
化合物40c之合成步驟 143
化合物41c之合成步驟 144
化合物42c之合成步驟 145
化合物28c之合成步驟 146
化合物46之合成步驟 147
化合物47之合成步驟 148
化合物29a之合成步驟 149
化合物48之合成步驟 150
化合物29b之合成步驟 151
化合物29c之合成步驟 152
化合物29d之合成步驟 153
柒、參考文獻………………………………………………………………………………… 154


附錄一、化合物之氫核磁共振圖…………………………………………………… 158
附錄二、化合物之質譜圖……………………………………………………………… 259
參考文獻 柒、參考文獻
1. World Health Organization http://www.who.int/mediacentre/factsheets/fs297/en/index.html
2. 行政院衛生署http://www.doh.gov.tw/cht2006/index_populace.aspx
3. U.S. Food and Drug Administration http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108758.htm
4. ClinicalTrials.gov http://clinicaltrials.gov/ct2/home
5. Haishan, W.; Brian, W. D. New patented histone deacetylase Inhibitors. Expert Opinion on Therapeutic Patents, 2009, 19, 1727-1757
6. De Ruijter, A. J. M.; Van Gennip, A. H.; Caron, H.N.; Kemp, S.; Van Kuilenburg, A. B. P. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochemistry Journal. 2003, 370, 737-749
7. Steve, P.; Hazel, J. D. Histone deacetylase inhibitors: an analysis of recent patenting activity. Expert Opinion on Therapeutic Patents, 2007, 17, 745-765
8. Becker, W. M., Lewis, J. K.,& Jeff, H. (Eds.). (2006). The World of the Cell, Benjamin Cummings, San Francisco, CA.
9. Caterino, T. L.; Jeffrey, J. H. Chromatin structure depends on what’s in the nucleosome’s pocket. Nature Structural and Molecular Biology, 2007, 14, 1056-1058
10. Lina, P.; Jun, L.; Baiqu, H. HDAC Inhibitors: A Potential New Category of Anti-Tumor Agents. Cellular and Molecular Immunology, 2007, 4, 337-343
11. Hoshino, I.; Matsubara, H. Recent Advances in Histone Deacetylase Targeted Cancer Therapy. Surgery Today, 2010, 40, 809-815
12. Xu, W. S.; Parmigiani, R. B.; Marks, P. A. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene, 2007, 26, 5541-5552
13. Andrew, A.L.; Bruce, A. C. Histone Deacetylase Inhibitors in Cancer Therapy. Journal of Clinical Oncology, 2009,27,5459-5468
14. Michael, H.; Rusty, L. M.; Eric, N. O. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nature reviews genetics, 2009, 10, 32-42
15. Greg, K. ND. A Review of the Sirtuin System, Its Clinical Implications, and the Potential Role of Dietary Activators like Resveratrol: Part 1. Alternative Medicine Review, 2010, 15, 245-263
16. Marielle, P.; Marina, P.; Monica, B.; Daniela, F. Histone Deacetylase Inhibitors: From Bench to Clinic. Journal of Medicinal Chemistry, 2008, 51, 1505-1529
17. Paola, G.; Stefania, D. M.; Phillip, J.; Michele, P.; Christian, S. HDACs, histone deacetylation and gene transcription: from molecular biology to cancer therapeutics. Cell Research, 2007, 17, 195-211
18. John, R. S.; Robert, J. S.; Bradley, A.K.; Clifford, M.; Joseph, D. H.; Andy, J. J.; Christine, L.; Andrew, A.; Joseph, J. B.; Ellen, C.; Jie, T.; Bi-ching Sang; Erik, V.; Robert, W.; Ellen, M. L.; Douglas, R. D.; Gyorgy, S.; Marc, N.; Mark, W. K.; Ronald, V. S.; Duncan, E. M.; Leslie, W. T. Structural Snapshots of Human HDAC8 Provide Insights into the Class I Histone Deacetylases. Structure, 2004, 12, 1325-1334
19. Alessandro, V.; Cinzia, V.; Gessica, F.; Elena, C. C.; Mirko, B.; Debora, R.; Prasum, C. ; Chantal, P.; Raffaele, D. F.; Paola, G. Christian, S.; Stefania D. M. Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. Proceedings of the National Academy of Sciences, 2004, 101, 15064-15069
20. Nieghat, N.; Hamid, R.; Saima, K. Identification of type-specific anticancer histone deacetylase inhibitors: road to success. Cancer chemotherapy and Pharmacology, 2010, 66, 625-633
21. Christian, H.; Daniel, R.; Andreas, S. Histone deacetylases-an important class of cellular regulators with a variety of functions. Applied Microbiology and Biotechnology, 2007, 75, 487-497
22. Liang, G.; Aidong, H.; Darren, L. B.; Jue, C.; Lin, C. Crystal structure of a conserved N-terminal domain of histone deacetylase 4 reveals functional insights into glutamine-rich domains. Proceedings of the National Academy of Sciences, 2007, 104, 4297-4302
23. Anja, S.; Jinrong, M;, Abdellah, A. H., Matthiey, S.; Michael, S.; Peter, L.; Ralph, M.; Nick, P. K.; Timothy, A. L.; Rebecca, L. M.; Thomas, H. M.; Alexey, B.; Alexander, N. P.; Masoud, V,; Cheryl, H.A. Human HDAC7 Harbors a Class IIa Histone Deacetylase-specific Zinc Binding Motif and Cryptic Deactylase activity, The Journal of Biological chemistry, 2008, 283, 11355-11363
24. Sonia, E.; Marianna, L.; Giovanni, T. Histone deacetylase inhibitors: Apoptotic effects and clinical implications (Review). International journal of oncology, 2008, 33, 637-646
25. Ulrich, M.; Dieter, H. Histone Acetylation Modifiers in the Pathogenesis of Malignant Disease. Molecular Medicine, 2000, 6, 623-644
26. Jazirehi, A. R. Regulation of apoptosis-associated genes by histone deacetylase inhibitors: implication in cancer therapy. Anti-Cancer Drugs, 2010, 21, 805-813
27. Daniela, B.; Anas, Younes. Hisone deacetylase inhibitors in Hodgkin lymphoma. Investigational New Drugs, 2010, 28, S21-S27
28. Omar, K.; Susan, F.; Victoria, W.; Lindsay, S.; Chunlei, Z.; Francesco, P.; Madeleine, D.; David, J. K.; Nicholas, B. L. T. HR23B is a biomarker for tumor sensitivity to HDAC inhibitor-based therapy. Proceedings of the National Academy of Sciences, 2010, 107, 6532-6537
29. Grace, I. A. M.; Kathleen, M. S. The Role of HDAC6 in Cancer. Journal of Biomedicine and Biotechnology, 2011, 2011 , 875-824
30. Carol, P.; James, L. M. Why Is p53 Acetylated? Cell, 2001, 107, 815-818
31. Milos, D.; Cathy, C.; Paul, A. M. Histone deacetylase Inhibitore: Overview and Perspectives. Molecular Cancer Research, 2007, 5,981-989
32. Olaia, M. I.; Lidia, R. L.; Ruth, S. M.; Laura, G.; Alberto, Z.; Ana, A. Histone deacetylase inhibitors: mechanism of action and therapeutic use in cancer. Clinical and Translational of oncology, 2008, 10, 395-398
33. Alisa J. F.; Ricky, W. J.; Jessica, E. B. Enhancing the apoptotic and therapeutic effects of HDAC inhibitors. Cancer Letters, 2009, 280, 125-133
34. Jennifer, S. C.; Francis, J. G.; Steffan , T. N. Histone deacetylase inhibitors: Mechanism of cell death and promise in combination cancer therapy. Cancer Letters, 2008, 269, 7-17
35. Paul, A. M.; Xuejun, J. Histone Deacetylase Inhibitors in Programmed Cell Death and Cancer Therapy. Cell Cycle, 2005, 4, 549-551
36. Ricky, W. J. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nature Reviews Drug Discovery, 2002, 1, 287-299
37. Kim, H. J.; Bae, S. C. Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs. American Journal of Translational Research, 2011, 3, 166-179
38. Xiaofu, W.; Lindsey, N. J.; Sara, M. J. Suppression of Neurotensin Receptor Type 1 Expression and Function by Histone Deacetylase Inhibitors in Human Colorectal Cancers. Molecular Cancer Therapeutics, 2010, 9, 2389-2398
39. Vivek, V.; Christian, R.; Lara, I.; Stefan, S.; Irfan, Y. T.; Jochen, W.; Oliver, W.; Thomas, A. B. Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein. The Journal of Biological Chemistry, 2010, 285, 10678-10689
40. Wagner, J. M.; Hackanson, B.; Lubbert, M.; Jung, M. Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy. Clinical Epigenetics, 2010, 1, 117-136
41. Lianne, F.; Purva, B.; Sylvie, W.; Sreenivase, D.; Fei, G.; Hirohito, Y.; Hong-gang, W.; Peter, A.; Kapil, B. Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B. Molecular Cancer Therapeutics, 2003, 2, 971-984
42. Xiaozhong, Q.; Wiliam, J. LaRochelle, Gulshan, A.; Frank, Wu; Kamille, D. P.; Annemette, T.; Maxwell, S.; Henri, S. L.; Michael, J. Activity of PXD101, a hitone deacetylase inhibitor, in preclinical ovarian cancer studies. Molecular Cancer Therapeutics, 2006, 5, 2086-95
43. Yonghua, Y.; Rehka, R.; Jie, S. Role of Acetylation and Extracellulr Location of Heat Shock Protein 90α in Tumor Cell Invasion. Cancer Research, 2008, 68, 4833-4842
44. Lemoine, M.; Younes, A. Histone deacetylase inhibitors in the treatment of lymphoma. Discovery Medicine, 2010, 10, 462-470
45. KeeMing, C.; Heather, B.; Kaneez, J.; Brian, G. The histone deacetylase inhibitor MGCD0103 has both deacetylase and microtubule inhibitory activity. Molecular Pharmacology, 2010, 78, 436-443
46. Chang, C. Y.; Hsieh, H. P.; Chang, C. Y.; Hsu, K. S.; Chiang, Y. F.; Chen, C. M.; Kuo, C. C.; Liou, J. P. 7-Aryol-aminoindoline-1-sulfonamides as a Novel Class of Potent Antitubulin Agents. Journal of Medicinal Chemistry, 2006, 49, 6656-6659
47. Hayamitsu A.; Krishnan K. P.; Andrei A. I.; Nathaniel, B.; Zhan-Guo, G.; Kenneth A. J. Structure-Activity Relationships of 2,N6,5’-Substituted Adenosine Derivatives with Potent Activity at the A2B Adenosine Receptor. Journal of Medicinal Chemistry, 2007, 50, 1810-1827
48. Gadarla R. R.; Kuo. C. C.; Tan, U. K.; Mohane S. C.; Chang, C. Y.; Chang, Y. K.; Lai, M. J.; Yeh, J. Y.; Wu, S. Y.; Chang, J. Y.; Liou, J. P.; Hsieh, H. P. Synthesis and Structure-Activity Relationship of 2-Amino-1-aroylnaphthalene and 2-Hydroxy-1-aroylnaphthalenes as Potent Antitubulin Agents. Journal of Medicinal Chemistry, 2008, 51, 8163-8167
49. Liou, J. P.; Neeraj, M.; Chang, C. W.; Guo, F. M.; Sandy Wen-Hsing Lee.; Tan, U. K.; Yeh, T. K.; Kuo. C. C.; Chang, Y. W.; Lu, P. H.; Tung, Y. S.; Ke-Ta Lin.; Chanf, J. Y. ; Hsieh, H. P. Structure-Activity Relationship Studies of 3-aroylindoles as Potent Antimitotic Agents. ChemMedChem, 2006, 1, 1106-1118
50. Lai, M. J.; Kuo, C. C.; Yeh, T. K.; Hsieh, H. P.; Chen, L. T.; Pan, W. Y,; Hsu, K. Y.,; Chang, J. Y.; Liou, J. P. Synthesis and Structure-Activity Relationship of 1-Benzyl-4,5,6-trimethoxyindoles as a Novel Class of Potent Antitubulin Agents. ChemMedChem, 2009, 4, 588-593
論文全文使用權限
  • 同意授權瀏覽/列印電子全文服務,於2016-08-18起公開。


  • 若您有任何疑問,請與我們聯絡!
    臺北醫學大學 圖書館 簡莉婷
    E-mail:etds@tmu.edu.tw
    Tel:(02) 2736-1661 ext.2519
    Fax:(02) 2737-5446