跳到主要內容

臺灣博碩士論文加值系統

(100.28.0.143) 您好!臺灣時間:2024/07/19 16:13
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:林芳儀
研究生(外文):Fang-Yi Lin
論文名稱:設計與合成喹喔啉衍生物作為G9a抑制劑
論文名稱(外文):Design and synthesize of quinoxaline derivatives as G9a inhibitors
指導教授:蕭崇瑋
指導教授(外文):Chuang-Wai Shiau
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生物藥學研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2020
畢業學年度:108
語文別:中文
論文頁數:33
中文關鍵詞:
相關次數:
  • 被引用被引用:0
  • 點閱點閱:62
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
目錄
摘要................................................................................................................................ I
Abstract.........................................................................................................................II
目錄..............................................................................................................................III
圖目錄...........................................................................................................................V
表目錄..........................................................................................................................VI
第一章 緒論..................................................................................................................1
第一節 組蛋白離胺酸甲基化..................................................................................1
第二節 G9a 結構與功能 ..........................................................................................3
第三節 G9a 與癌症關聯 ..........................................................................................6
第四節 G9a 抑制劑 ..................................................................................................8
第二章 研究目標及設計概念....................................................................................11
第三章研究結果..........................................................................................................12
第一節 新化合物之化學合成................................................................................12
第二節 新化合物之生物活性探討........................................................................13
第四章 結果討論........................................................................................................20
第五章 實驗材料與方法............................................................................................22
第一節 藥品與器材................................................................................................22
第二節 化合物純化與鑑定....................................................................................23
第三節 生物活性測試............................................................................................25
第六章 參考文獻........................................................................................................27


圖目錄
圖 1:組蛋白離胺酸甲基轉移酶將 SAM 的甲基轉移至離胺酸殘基.....................2
圖 2:G9a 的結構........................................................................................................3
圖 3:HP1 辨識 H3K9me2 並招募 DNMT 3a/b 抑制基因轉錄之機制 ...................4
圖 4:G9a 的 ankyrin repeat domain 辨識 H3K9me2 並招募 DNMT 3a/b 抑制基因
轉錄之機制............................................................................................................5
圖 5:G9a 自我甲基化 automethylation site 後,HP1 辨識 H3K9me2 並招募 DNMT
3a/b 抑制基因轉錄之機制....................................................................................5
圖 6:G9a 受質競爭抑制劑結構................................................................................8
圖 7:SAM 與 SAM 競爭抑制劑結構 .......................................................................8
圖 8:G9a 抑制劑-G9a 複合物之結晶結構.............................................................10
圖 9:新化合物 9B、11B 和 11A 對於 SNU449 細胞株之細胞群落形成影響。16
圖 10:新化合物作用於 SNU449 細胞株 48 小時之 G9a 和 H3K9me2 蛋白表現。
..............................................................................................................................18
圖 11:新化合物作用於 SNU449 細胞株 24 小時之 G9a 和 H3K9me2 蛋白表現。
..............................................................................................................................19

表目錄
表 1:新化合物產率比較.............................................12
表 2:新化合物 A 系列之肝癌細胞 SNU449 毒殺性比較。 ................13
表 3:新化合物 B 系列之肝癌細胞 SNU449 毒殺性比較。 ................14
表 4:新化合物 C 系列之肝癌細胞 SNU449 毒殺性比較。 ................15
1. Zentner GE, Henikoff S. Regulation of nucleosome dynamics by histone
modifications. Nat Struct Mol Biol. 2013;20(3):259-266.
2. Shiio Y, Eisenman RN. Histone sumoylation is associated with transcriptional
repression. Proc Natl Acad Sci U S A. 2003;100(23):13225-13230.
3. Biran A, Meshorer E. Concise review: chromatin and genome organization in
reprogramming. Stem Cells. 2012;30(9):1793-1799.
4. Jenuwein T, Allis CD. Translating the histone code. Science.
2001;293(5532):1074-1080.
5. Martin C, Zhang Y. The diverse functions of histone lysine methylation. Nat Rev
Mol Cell Biol. 2005;6(11):838-849.
6. Liu Q, Wang MW. Histone lysine methyltransferases as anti-cancer targets for
drug discovery. Acta Pharmacol Sin. 2016;37(10):1273-1280.
7. Xiong Y, Li F, Babault N, et al. Discovery of Potent and Selective Inhibitors for
G9a-Like Protein (GLP) Lysine Methyltransferase. J Med Chem. 2017;60(5):1876-
1891.
8. Black JC, Van Rechem C, Whetstine JR. Histone lysine methylation dynamics:
establishment, regulation, and biological impact. Mol Cell. 2012;48(4):491-507.
9. Mozzetta C, Boyarchuk E, Pontis J, Ait-Si-Ali S. Sound of silence: the properties
and functions of repressive Lys methyltransferases. Nat Rev Mol Cell Biol.
2015;16(8):499-513.
10. Rea S, Eisenhaber F, O'Carroll D, et al. Regulation of chromatin structure by sitespecific histone H3 methyltransferases. Nature. 2000;406(6796):593-599.
11. Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications.
Cell Res. 2011;21(3):381-395.
12. Copeland RA, Solomon ME, Richon VM. Protein methyltransferases as a target
class for drug discovery. Nat Rev Drug Discov. 2009;8(9):724-732.
13. Fog CK, Jensen KT, Lund AH. Chromatin-modifying proteins in cancer. Apmis.
2007;115(10):1060-1089.
14. Spannhoff A, Sippl W, Jung M. Cancer treatment of the future: inhibitors of
histone methyltransferases. Int J Biochem Cell Biol. 2009;41(1):4-11.
15. Li Y, Reddy MA, Miao F, et al. Role of the histone H3 lysine 4 methyltransferase,
SET7/9, in the regulation of NF-kappaB-dependent inflammatory genes. Relevance to
diabetes and inflammation. J Biol Chem. Vol. 283; 2008:26771-26781.
16. Schaefer A, Sampath SC, Intrator A, et al. Control of cognition and adaptive
behavior by the GLP/G9a epigenetic suppressor complex. Neuron. 2009;64(5):678-691.
17. Imai K, Togami H, Okamoto T. Involvement of histone H3 lysine 9 (H3K9)
methyltransferase G9a in the maintenance of HIV-1 latency and its reactivation by
BIX01294. J Biol Chem. 2010;285(22):16538-16545.
18. McGarvey KM, Fahrner JA, Greene E, Martens J, Jenuwein T, Baylin SB.
Silenced tumor suppressor genes reactivated by DNA demethylation do not return to a
fully euchromatic chromatin state. Cancer Res. 2006;66(7):3541-3549.
19. Kondo Y, Shen L, Ahmed S, et al. Downregulation of histone H3 lysine 9
methyltransferase G9a induces centrosome disruption and chromosome instability in
cancer cells. PLoS One. 2008;3(4):e2037.
20. Casciello F, Windloch K, Gannon F, Lee JS. Functional Role of G9a Histone
Methyltransferase in Cancer. Front Immunol. 2015;6:487.
21. Scheer S, Zaph C. The Lysine Methyltransferase G9a in Immune Cell
Differentiation and Function. Front Immunol. 2017;8:429.
22. Barski A, Cuddapah S, Cui K, et al. High-resolution profiling of histone
methylations in the human genome. Cell. 2007;129(4):823-837.
23. Kramer JM. Regulation of cell differentiation and function by the euchromatin
histone methyltranserfases G9a and GLP. Biochem Cell Biol. 2016;94(1):26-32.
24. Purcell DJ, Jeong KW, Bittencourt D, Gerke DS, Stallcup MR. A distinct
mechanism for coactivator versus corepressor function by histone methyltransferase
G9a in transcriptional regulation. J Biol Chem. 2011;286(49):41963-41971.
25. Bittencourt D, Wu DY, Jeong KW, et al. G9a functions as a molecular scaffold for
assembly of transcriptional coactivators on a subset of glucocorticoid receptor target
genes. Proc Natl Acad Sci U S A. 2012;109(48):19673-19678.
26. Collins RE, Tachibana M, Tamaru H, et al. In vitro and in vivo analyses of a
Phe/Tyr switch controlling product specificity of histone lysine methyltransferases. J
Biol Chem. 2005;280(7):5563-5570.
27. Milner CM, Campbell RD. The G9a gene in the human major histocompatibility
complex encodes a novel protein containing ankyrin-like repeats. Biochem J. 1993;290
( Pt 3):811-818.
28. Lanouette S, Mongeon V, Figeys D, Couture JF. The functional diversity of protein
lysine methylation. Mol Syst Biol. 2014;10:724.
29. Xiong Y, Li F, Babault N, et al. Structure-activity relationship studies of G9a-like
protein (GLP) inhibitors. Bioorg Med Chem. 2017;25(16):4414-4423.
30. Tachibana M, Ueda J, Fukuda M, et al. Histone methyltransferases G9a and GLP
form heteromeric complexes and are both crucial for methylation of euchromatin at H3-
K9. Genes Dev. 2005;19(7):815-826.
31. Tachibana M, Matsumura Y, Fukuda M, Kimura H, Shinkai Y. G9a/GLP
complexes independently mediate H3K9 and DNA methylation to silence transcription.
Embo j. 2008;27(20):2681-2690.
32. Tachibana M, Nozaki M, Takeda N, Shinkai Y. Functional dynamics of H3K9
methylation during meiotic prophase progression. Embo j. 2007;26(14):3346-3359.
33. Tachibana M, Sugimoto K, Nozaki M, et al. G9a histone methyltransferase plays
a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for
early embryogenesis. Genes Dev. 2002;16(14):1779-1791.
34. Thomas LR, Miyashita H, Cobb RM, et al. Functional analysis of histone
methyltransferase g9a in B and T lymphocytes. J Immunol. 2008;181(1):485-493.
35. Benevento M, van de Molengraft M, van Westen R, van Bokhoven H, Kasri NN.
The role of chromatin repressive marks in cognition and disease: A focus on the
repressive complex GLP/G9a. Neurobiol Learn Mem. 2015;124:88-96.
36. Lachner M, O'Carroll D, Rea S, Mechtler K, Jenuwein T. Methylation of histone
H3 lysine 9 creates a binding site for HP1 proteins. Nature. 2001;410(6824):116-120.
37. Maison C, Almouzni G. HP1 and the dynamics of heterochromatin maintenance.
Nat Rev Mol Cell Biol. 2004;5(4):296-304.
38. Brenner C, Fuks F. A methylation rendezvous: reader meets writers. Dev Cell.
2007;12(6):843-844.
39. Epsztejn-Litman S, Feldman N, Abu-Remaileh M, et al. De novo DNA
methylation promoted by G9a prevents reprogramming of embryonically silenced
genes. Nat Struct Mol Biol. 2008;15(11):1176-1183.
40. Chin HG, Esteve PO, Pradhan M, et al. Automethylation of G9a and its implication
in wider substrate specificity and HP1 binding. Nucleic Acids Res. 2007;35(21):7313-
7323.
41. El Gazzar M, Yoza BK, Chen X, Hu J, Hawkins GA, McCall CE. G9a and HP1
couple histone and DNA methylation to TNFalpha transcription silencing during
endotoxin tolerance. J Biol Chem. 2008;283(47):32198-32208.
42. Kanwal R, Gupta K, Gupta S. Cancer epigenetics: an introduction. Methods Mol
Biol. 2015;1238:3-25.
43. Casciello F, Al-Ejeh F, Kelly G, et al. G9a drives hypoxia-mediated gene
repression for breast cancer cell survival and tumorigenesis. Proc Natl Acad Sci U S A.
2017;114(27):7077-7082.
44. Hu L, Zang MD, Wang HX, et al. G9A promotes gastric cancer metastasis by
upregulating ITGB3 in a SET domain-independent manner. Cell Death Dis.
2018;9(3):278.
45. Li F, Zeng J, Gao Y, et al. G9a Inhibition Induces Autophagic Cell Death via
AMPK/mTOR Pathway in Bladder Transitional Cell Carcinoma. PLoS One.
2015;10(9):e0138390.
46. Yokoyama M, Chiba T, Zen Y, et al. Histone lysine methyltransferase G9a is a
novel epigenetic target for the treatment of hepatocellular carcinoma. Oncotarget.
2017;8(13):21315-21326.
47. Wei L, Chiu DK, Tsang FH, et al. Histone methyltransferase G9a promotes liver
cancer development by epigenetic silencing of tumor suppressor gene RARRES3. J
Hepatol. 2017;67(4):758-769.
48. Chen RJ, Shun CT, Yen ML, Chou CH, Lin MC. Methyltransferase G9a promotes
cervical cancer angiogenesis and decreases patient survival. Oncotarget.
2017;8(37):62081-62098.
49. Huang T, Zhang P, Li W, et al. G9A promotes tumor cell growth and invasion by
silencing CASP1 in non-small-cell lung cancer cells. Cell Death Dis. 2017;8(4):e2726.
50. Qin J, Zeng Z, Luo T, Li Q, Hao Y, Chen L. Clinicopathological significance of
G9A expression in colorectal carcinoma. Oncol Lett. 2018;15(6):8611-8619.
51. Chen H, Yan Y, Davidson TL, Shinkai Y, Costa M. Hypoxic stress induces
dimethylated histone H3 lysine 9 through histone methyltransferase G9a in mammalian
cells. Cancer Res. 2006;66(18):9009-9016.
52. Chen MW, Hua KT, Kao HJ, et al. H3K9 histone methyltransferase G9a promotes
lung cancer invasion and metastasis by silencing the cell adhesion molecule Ep-CAM.
Cancer Res. 2010;70(20):7830-7840.
53. Wozniak RJ, Klimecki WT, Lau SS, Feinstein Y, Futscher BW. 5-Aza-2′-
deoxycytidine-mediated reductions in G9A histone methyltransferase and histone H3
K9 di-methylation levels are linked to tumor suppressor gene reactivation. Oncogene.
2006;26(1):77-90.
54. Dong C, Wu Y, Yao J, et al. G9a interacts with Snail and is critical for Snailmediated E-cadherin repression in human breast cancer. J Clin Invest.
2012;122(4):1469-1486.
55. Liu S, Ye D, Guo W, et al. G9a is essential for EMT-mediated metastasis and
maintenance of cancer stem cell-like characters in head and neck squamous cell
carcinoma. Oncotarget. 2015;6(9):6887-6901.
56. Zhang J, Wang Y, Shen Y, He P, Ding J, Chen Y. G9a stimulates CRC growth by
inducing p53 Lys373 dimethylation-dependent activation of Plk1. Theranostics.
2018;8(10):2884-2895.
57. Hasan NM, Adams GE, Joiner MC, Marshall JF, Hart IR. Hypoxia facilitates
tumour cell detachment by reducing expression of surface adhesion molecules and
adhesion to extracellular matrices without loss of cell viability. Br J Cancer.
1998;77(11):1799-1805.
58. Srimongkolpithak N, Sundriyal S, Li F, Vedadi M, Fuchter MJ. Identification of
2,4-diamino-6,7-dimethoxyquinoline derivatives as G9a inhibitorsdaggerElectronic
supplementary information (ESI) available. See DOI: 10.1039/c4md00274a.
Medchemcomm. 2014;5(12):1821-1828.
59. Chang Y, Zhang X, Horton JR, et al. Structural basis for G9a-like protein lysine
methyltransferase inhibition by BIX-01294. Nat Struct Mol Biol. 2009;16(3):312-317.
60. Kubicek S, O'Sullivan RJ, August EM, et al. Reversal of H3K9me2 by a smallmolecule inhibitor for the G9a histone methyltransferase. Mol Cell. 2007;25(3):473-
481.
61. Oh SY, Seok JY, Choi YS, Lee SH, Bae JS, Lee YM. The Histone
Methyltransferase Inhibitor BIX01294 Inhibits HIF-1alpha Stability and Angiogenesis.
Mol Cells. 2015;38(6):528-534.
62. Kim Y, Kim YS, Kim DE, et al. BIX-01294 induces autophagy-associated cell
death via EHMT2/G9a dysfunction and intracellular reactive oxygen species
production. Autophagy. 2013;9(12):2126-2139.
63. Ueda J, Ho JC, Lee KL, et al. The hypoxia-inducible epigenetic regulators Jmjd1a
and G9a provide a mechanistic link between angiogenesis and tumor growth. Mol Cell
Biol. 2014;34(19):3702-3720.
64. Liu F, Chen X, Allali-Hassani A, et al. Discovery of a 2,4-diamino-7-
aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine
methyltransferase G9a. J Med Chem. 2009;52(24):7950-7953.
65. Cao H, Li L, Yang D, et al. Recent progress in histone methyltransferase (G9a)
inhibitors as anticancer agents. Eur J Med Chem. 2019;179:537-546.
66. Liu XR, Zhou LH, Hu JX, Liu LM, Wan HP, Zhang XQ. UNC0638, a G9a inhibitor,
suppresses epithelialmesenchymal transitionmediated cellular migration and invasion
in triple negative breast cancer. Mol Med Rep. 2018;17(2):2239-2244.
67. Vedadi M, Barsyte-Lovejoy D, Liu F, et al. A chemical probe selectively inhibits
G9a and GLP methyltransferase activity in cells. Nat Chem Biol. 2011;7(8):566-574.
68. Liu F, Barsyte-Lovejoy D, Li F, et al. Discovery of an in vivo chemical probe of
the lysine methyltransferases G9a and GLP. J Med Chem. 2013;56(21):8931-8942.
69. Qin J, Li Q, Zeng Z, et al. Increased expression of G9A contributes to
carcinogenesis and indicates poor prognosis in hepatocellular carcinoma. Oncol Lett.
2018;15(6):9757-9765
連結至畢業學校之論文網頁點我開啟連結
註: 此連結為研究生畢業學校所提供,不一定有電子全文可供下載,若連結有誤,請點選上方之〝勘誤回報〞功能,我們會盡快修正,謝謝!
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top