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姓名	施政廷(Cheng-Ting Shih)  查詢紙本館藏	畢業系所	化學學系
論文名稱	發展八環 1,2-雙酮化學探針分子 選擇性標定含胍基化合物及其後續應用 (Development of Dibenzocyclooctendione-based Probes for Specific Labeling of Arginine-Containing Molecules and Its Applications)
檔案	[Endnote RIS 格式]    [Bibtex 格式]    [相關文章]   [文章引用]   [完整記錄]   [館藏目錄]   至系統瀏覽論文 (2027-12-31以後開放)
摘要(中)	胍基常見於精胺酸(arginine)、胜肽、蛋白質以及生物分子中；蛋白質後轉譯修飾的精胺酸，其側鏈末端的胍基會轉變為脲(urea)官能基或進行甲基化，此代謝修飾已證實與疾病有所關連，例如:類風濕性關節炎、潰瘍性結腸炎、阿茲海默症、狼瘡或是癌症等，因此近年來有許多科學家致力於胍基的標定，然而大部分標定的反應需要強鹼或高溫等嚴苛的反應環境，所產生的不穩定加成產物也會因反應環境而緩慢水解，以上的因素也限制了它們在生物標定上的應用。在本論文中，我們合成ㄧ系列八環 1,2-雙酮的衍生物，在溫和的條件下，可與含胍基的化合物進行脫水重排反應，形成穩定的加成產物。另一方面，利用不同官能基取代的八環 1,2-雙酮衍生物，針對 1-甲基脲、1-甲基胍鹽酸鹽、1,2-二甲基胍氫溴酸鹽以及 1,1-二甲基胍鹽酸鹽探討其反應性；最後我們也將疊氮分子利用聚乙二醇鏈引入八環 1,2-雙酮衍生物，以便後續利用疊氮-炔烴環加成反應接上螢光團或是當作藥物-抗體偶聯物的修飾應用。
摘要(英)	Guanidine is a small nitrogen-rich small compound and extremely common in biological systems. Guanidine functional groups are also frequently present in natural products, bioactive compounds and one of the most important pharmacophoric groups in medicinal chemistry. Furthermore, arginine citrullination and methylation are two universal post‑translational modifications on the side chain of arginine in natural peptides and proteins. Aberrant protein citrullination is relevant to several autoimmune and neurodegenerative diseases as well as some cancer formations. Aberrant histone arginine methylation is associated with carcinogenesis and metastasis have been well demonstrated. Until now, several studies have investigated the reactivity of arginine to various reagents for the chemical modifications of guanidine group of arginine in biomolecules. However, most of the labeling conditions are under strong base or high temperature harsh conditions that are not suitable for biological applications. In this thesis, we develop eight-membered 1,2-diketone derivatives (DBCDOs), which underwent an irreversible ring-contracted rearrangement with the guanidine group on arginine residue under mild reaction conditions. We also explore the reactivity of these 1,2-diketone probe derivatives and 1-methylurea, 1-methylguanidine hydrochloride, 1,2-dimethylguanidine hydrobromide and 1,1-dimethylguanidine hydrochloride. Finally, we also introduced the azide group into the eight-membered 1,2-diketone derivative by using the polyethylene glycol chain for subsequent applications, such as attachment of a fluorophore or as a drug-antibody conjugates.
關鍵字(中)	★ 胍基 ★ 精胺酸 ★ 後轉譯修飾 ★ 1,2-雙酮 ★ 螢光團 ★ 抗體-藥物偶聯物 ★ 疊氮-炔烴環加成反應	關鍵字(英)	★ guanidine group ★ arginine ★ post-translational modification ★ 1,2-diketone ★ fluorophore ★ antibody-drug conjugates ★ azide-alkyne cycloaddition reaction
論文目次	摘要.........................................................................................................................................i Abstract....................................................................................................................................ii 誌謝....................................................…...................................................................................iii 目錄.........................................................................................................................................iv 圖目錄......................................................................................................................................vii 表目錄........................................................................................................................................x 簡稱用語對照表...............................................................................................................................xi 一、 緒論.....................................................................................................................................1 1-1 前言.....................................................................................................................................1 1-2 點擊化學(click chemistry)................................................................................................................2 1-2-1 銅催化疊氮-炔烴環加成反應(Copper(I)-Assisted Azide-Alkyne Cycloaddition, CuAAC)........................................................................................................................2 1-2-2 環張力促進疊氮-炔烴環加成反應(Strain-Promoted Azide-Alkyne Cycloaddition, SPAAC).......................................................................................................................................3 1-2-3 施陶丁格反應(Staudinger reaction)......................................................................................................3 1-3 胺基酸的偶聯反應..........................................................................................................................4 1-3-1 離胺酸(lysine)的偶聯反應................................................................................................................5 1-3-2 半胱胺酸(cysteine)的偶聯反應............................................................................................................6 1-3-3 酪胺酸(tyrosine)的偶聯反應..............................................................................................................7 1-4 胍(guanidine)與其衍生物的介紹.............................................................................................................8 1-5 胍官能基(guanidine group)的偶聯反應.......................................................................................................9 1-6 研究動機................................................................................................................................13 二、 實驗結果與討論..........................................................................................................................…14 2-1 八環1,2-雙酮衍生物的合成..................................................................................................................14 2-1-1 化合物 2 的合成........................................................................................................................14 2-1-2 化合物 4 的合成........................................................................................................................15 2-1-3 化合物 12 的合成.......................................................................................................................15 2-2 八環1,2-雙酮衍生物對於精胺酸轉譯後修飾官能基的標定探討.......................................................................................17 2-2-1 八環 1,2-雙酮分子對於 1-甲基脲的標定…....................................................................................................18 2-2-2 八環 1,2-雙酮分子對於 1-甲基胍鹽酸鹽的標定………............................................................................................18 2-2-3 八環 1,2-雙酮分子對於 1,2-二甲基胍氫溴酸鹽的標定……….......................................................................................20 2-2-4 八環 1,2-雙酮分子對於 1,1-二甲基胍鹽酸鹽的標定............................................................................................21 2-3 1,2-雙酮分子對於其他含胍基化合物的標定效果.................................................................................................22 2-3-1 八環 1,2-雙酮分子對於左旋精胺酸(L-arginine)鹽酸鹽的標定...................................................................................22 2-3-2 八環 1,2-雙酮分子對於肌酸(creatine)的標定................................................................................................23 2-3-3 八 環 1,2- 雙 酮 分 子 對 於 苯 基 乙 內 醯 硫 脲 - 精 胺 酸 (PTH-arginine) 的 標 定...........................................................................................................................................24 2-3-3-1 化合物4 對於苯基乙內醯硫脲-精胺酸(PTH-arginine)的標定..................................................................................25 2-3-3-2 化合物2 對於苯基乙內醯硫脲-精胺酸(PTH-arginine)的標定..................................................................................27 2-3-4 八 環 1,2- 雙 酮 分 子 對 於 RGD 三 肽 (arginylglycylaspartic acid) 的 標 定...........................................................................................................................................28 2-3-4-1 化 合 物 4 對 於 RGD 三 肽 (arginylglycylaspartic acid) 的 標 定...........................................................................................................................................28 2-3-4-2 化 合 物 2 對 於 RGD 三 肽 (arginylglycylaspartic acid) 的 標 定...........................................................................................................................................30 2-3-5 八環 1,2-雙酮分子對於亮丙瑞林(leuprorelin acetate)的標定................................................................................31 2-3-5-1 化合物4對於亮丙瑞林(leuprorelin acetate)的標定........................................................................................31 2-3-5-2 化合物2對於亮丙瑞林(leuprorelin acetate)的標定.......................................................................................33 2-4 反應機構的探討...........................................................................................................................34 2-5 八環1,2-雙酮分子的後續發展...............................................................................................................36 2-5-1 化合物 34 的合成......................................................................................................................37 2-5-2 化合物 39 的合成......................................................................................................................38 2-5-3 化合物 44 的合成......................................................................................................................39 2-5-4 化合物 48 的合成......................................................................................................................42 2-6 八環1,2-雙酮分子的其他應用................................................................................................................44 2-7 結論....................................................................................................................................47 三、 實驗部分................................................................................................................................48 3-1 實驗儀器................................................................................................................................48 3-1-1 核磁共振光譜儀(nuclear magnetic resonance spectroscopy, NMR)..........................................................................48 3-1-2 高解析質譜儀(mass spectrometry).......................................................................................................49 3-1-3 傅 立 葉 轉 換 紅 外 光 譜 儀 (Fourier transform infrared red spectrometer, FTIR).......................................................................................................................................49 3-1-4 高 效 能 液 相 層 析 系 統 (high performance liquid chromatography system).....................................................................................................................................49 3-1-5 單晶 X-光繞射儀(single crystal X-ray diffractometer)..................................................................................49 3-1-6 自動旋光度計(digital polarimeter).....................................................................................................49 3-1-7 紫外-可見光光譜儀(UV-Vis spectroscopy).................................................................................................50 3-1-8 螢光光譜儀(flourescence spectroscopy).................................................................................................50 3-2 實驗藥品................................................................................................................................50 3-2-1 實驗藥品試劑..........................................................................................................................50 3-2-2 薄層色層分析(thin layer chromatography, TLC)..........................................................................................50 3-2-3 管柱色層分析(column chromatography)...................................................................................................50 3-3 合成步驟與光譜資料.......................................................................................................................51 參考文獻.....................................................................................................................................84 附錄一.......................................................................................................................................92 附錄二......................................................................................................................................169
參考文獻	[1] Kolb, H.-C.; Finn, M.-G.; Sharpless, K.-B. “Click Chemistry: Diverse Chemical Function from a Few Good Reactions.” Angew. Chem. Int. Ed. 2001, 40, 2004‒2021. [2] Worell, B.-T.; Malik, J.-A.; Fokin, V.-V. “Direct Evidence of a Dinuclear Copper Intermediate in Cu(I)-Catalyzed Azide-Alkyne Cycloadditions.” Science 2013, 340, 457‒460. [3] 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. 2004, 126, 15046–15047. [4] Staudinger, H.; Meyer, J. “Über neue organische Phosphorverbindungen III. Phosphinmethylenderivate und Phosphinimine.” Helv. Chim. Acta. 1919, 2, 635‒646. [5] Saxon, E.; Bertozzi, C.-R. “Cell Surface Engineering by a Modified Staudinger Reaction.” Science 2000, 287, 2007‒2010. [6] Joubert, N.; Beck, A.; Dumontet, C.; Denevault-Sabourin, C. “Antibody-Drug Conjugates: The Last Decade.” Pharmaceuticals 2020, 13, 245. [7] Stephanopoulos, N.; Francis, M.-B. “Choosing an effective protein bioconjugation strategy.” Nat. Chem. Biol. 2011, 7, 876–884. [8] Haque, M.; Forte, N.; Baker, J.-R. “Site-selective lysine conjugation methods and applications towards antibody–drug conjugates.” Chem. Commun. 2021, 57, 10689‒10702. [9] Shiu, H.-Y.; Chan, T.-C.; Ho, C.-M.; Liu, Y.; Wong, M.-K.; Che, C.-M. “ElectronDeficient Alkynes as Cleavable Reagents for the Modification of Cysteine-Containing Peptides in Aqueous Medium.” Chem. Eur. J. 2009, 15, 3839‒3850. [10] Koniev, O.; Leriche, G.; Nothisen, M.; Remy, J.-S.; Strub, J.-M.; Schaeffer-Reiss, C.; Dorsselaer, A.; Baati, R.; Wagner, A. “Selective Irreversible Chemical Tagging of Cysteine with 3-Arylpropiolonitriles.” Bioconjug. Chem. 2014, 25, 202−206. [11] Ban, H.; Nagano, M.; Gavrilyuk, J.; Hakamata, W.; Inokuma, T.; Barbas, C.-F. “Facile and Stabile Linkages through Tyrosine: Bioconjugation Strategies with the TyrosineClick Reaction.” Bioconjug. Chem. 2013, 24, 520–532. [12] Joshi, N.-S.; Whitaker, L.-R.; Francis, M.-B. “A Three-Component Mannich-Type Reaction for Selective Tyrosine Bioconjugation.” J. Am. Chem. Soc. 2004, 126, 15942–15943. [13] Berlinck, R.-G.-S.; Kossuga, M.-H. “Natural guanidine derivatives.” Nat. Prod. Rep. 2005, 22, 516–550. [14] Bicker, K.-L.; Thompson, P.-R. “The protein arginine deiminases (PADs): Structure, Function, Inhibition, and Disease.” Biopolymers 2013, 99, 155–163. [15] Grundler, V.; Gademann, K. “Direct Arginine Modification in Native Peptides and Application to Chemical Probe Development.” ACS Med. Chem. Lett. 2014, 5, 1290−1295. [16] Sibbersen, C.; Palmfeldt, J.; Hansen, J.; Gregersen, N.; Jørgensena, K.-A.; Johannsen, M. “Development of a chemical probe for identifying protein targets of α-oxoaldehydes.” Chem. Commun. 2013, 49, 4012‒4014. [17] Hwang, D.; Nilchan, N.; Nanna, A.-R.; Li, X.; Cameron, M.-D.; Roush, W.-R.; Park, H.; Rader, C. “Site-Selective Antibody Functionalization via Orthogonally Reactive Arginine and Lysine Residues.” Cell Chem. Biol. 2019, 26, 1229–1239. [18] Thompson, D.-A.; Ng, R.; Dawson, P.-E. “Arginine selective reagents for ligation to peptides and proteins.” J. Pept. Sci. 2016, 22, 311–319. [19] Wanigasekara, M.-S.-K.; Chowdhury, S.-M. “Evaluation of chemical labeling methods for identifying functional arginine residues of proteins by mass spectrometry.” Anal. Chim. Acta. 2016, 935, 197‒206. [20] Quagliato, D.-A.; Andrae, P.-M.; Fan Y. (2007), US Appl. Patent, US20070203116A1. [21] Mbua, N.-E.; Guo, J.; Wolfert, M.-A.; Steet, R.; Boons, G.-J. “Strain-Promoted AlkyneAzide Cycloadditions (SPAAC) Reveal New Features of Glycoconjugate Biosynthesis.” ChemBioChem. 2011, 12, 1912‒1921. [22] Slade, D.-J.; Subramanian, V.; Fuhrmann, J., Thompson, P.-R. “Chemical and biological methods to detect post-translational modifications of arginine.” Biopolymers 2014, 101,133‒143. [23] Mold, J.-D.; Ladino, J.-M.; Schantz, E.-J. “The Sakaguchi and Biacetyl Reactions for the Identification of Alkyl Guanidines.” J. Am. Chem. Soc. 1953, 75, 6321–6322. [24] Souza, M.-C.; Macedo, W.-P.; Silva, M.-C.-M.; Ramos, G.-C.-O.; Alt, H.-G. “One-pot synthesis of N-alkyl substituted phophoryl guanidines.” Phosphorus Sulfur Silicon Relat. Elem. 2004, 179, 1047‒1054. [25] Andrew, P.-J.; Mayer, B. “Enzymatic function of nitric oxide synthases.” Cardiovasc. Res. 1999, 43, 521‒531. [26] Gokce, N. “L-Arginine and Hypertension.” J. Nutr. 2004, 134, 2807S–2811S. [27] Alba-Roth, J.; Müller, O.-A.; Schopohl, J.; von Werder, K. “Arginine stimulates growth hormone secretion by suppressing endogenous somatostatin secretion.” J. Clin. Endocr. 1988, 67, 1186–1189. [28] Barcelos, R.-P.; Stefanello, S.-T.; Mauriz, J.-L.; Gonzalez-Gallego, J.; Soares, F.-A.-A. “Creatine and the Liver: Metabolism and Possible Interactions.” Mini-Rev. Med. Chem. 2016, 16, 12‒18. [29] Wallimann, T.; Wyss, M.; Brdiczka, D.; Nicolay, K.; Eppenberger, H.-M. “Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the ‘phosphocreatine circuit’ for cellular energy homeostasis.” Biochem. J. 1992, 281, 21–40. [30] Kley, R.-A.; Tarnopolsky M.-A.; Vorgerd M. “Creatine for treating muscle disorders.”Cochrane Database Syst. Rev. 2013, 6. [31] Cooper, R.; Naclerio, F.; Allgrove, J.; Jimenez, A. “Creatine supplementation with specific view to exercise/sports performance: an update.” J. Int. Soc. Sports Nutr. 2012, 9, 33. [32] Edman, P.; Högfeldt, E.; Sillén, L.-G.; Kinell, P.-O. “Method for Determination of the Amino Acid Sequence in Peptides.” Acta Chem. Scand. 1950, 4, 283–293. [33] Ruoslahti, E.; Pierschbacher, M.-D. “Arg-Gly-Asp: A Versatile Cell Recognition Signal.” Cell 1986, 44, 517‒518. [34] Fischer, J; Ganellin, C.-R. Analogue-based Drug Discovery; John Wiley & Sons, 2006, pp 514. [35] Crosignani, P.-G.; Luciano, A.; Ray, A.; Bergqvist, A. “Subcutaneous depot medroxyprogesterone acetate versus leuprolide acetate in the treatment of endometriosisassociated pain.” Hum. Reprod. 2005, 21, 248–256. [36] Theil, A.; Hitce, J.; Retailleau, P.; Marinetti, A. “A Synthetic Approach to Macrocyclic, Chiral Phosphane Derivatives with Crown-Ether-Like Structures.” Eur. J. Org. Chem. 2006, 154–161. [37] Srinivasan, N.-S.; Lee, D.-G. “Preparation of 1,2-Diketones: Oxidation of Alkynes by Potassium Permanganate in Aqueous Acetone.” J. Org. Chem. 1979, 44, 1574. [38] Abellán-Flos, M.; Tanç, M.; Supuran, C.-T.; Vincent, S.-P. “Exploring carbonic anhydrase inhibition with multimeric coumarins displayed on a fullerene scaffold.” Org. Biomol. Chem. 2015, 13, 7445‒7451. [39] Poloukhtine, A.-A.; Mbua, N.-E.; Wolfert, M.-A.; Boons, G.-J.; Popik, V.-V. “Selective Labeling of Living Cells by a Photo-Triggered Click Reaction.” J. Am. Chem. Soc. 2009, 131, 15769–15776. [40] Rokka, J.; Snellman, A.; Zona, C.; La Ferla, B.; Nicotra, F.; Salmona, M.; Forloni, G.; Haaparanta-Solin, M.; Rinne, J.; Solin, O. “Synthesis and evaluation of a 18F-curcumin derivate for β-amyloid plaque imaging.” Bioorg. Med. Chem. 2014, 22, 2753‒2762. [41] Davis, M.-A.; Winthrop, S.-O.; Thomas, R.-A.; Herr, F.; Charest, M.-P.; Gaudry, R. “Anticonvulsants. II. Spiro Compounds. Dibenzo[α,d]cycloheptadiene-5,5′-hydantoins,-5,5′-oxazolidinediones, and -5,2′-succinimides.” J. Med. Chem. 1964, 7, 439–445. [42] Bononi, G.; Granchi, C.; Lapillo, M.; Giannotti, M.; Nieri, D.; Fortunato, S.; Boustani, M.-E.; Caligiuri, I.; Poli, G.; Carlson, K.-E.; Kim, S.-H.; Macchia, M.; Martinelli, A.; Rizzolio, F.; Chicca, A.; Katzenellenbogen, J.-A.; Minutolo, F.; Tuccinardi, T. “Discovery of long-chain salicylketoxime derivatives as monoacylglycerol lipase (MAGL) inhibitors.” Eur. J. Med. Chem. 2018, 157, 817‒836. [43] Kang, D.; Kim, J. “Bioorthogonal Retro-Cope Elimination Reaction of N,NDialkylhydroxylamines and Strained Alkynes.” J. Am. Chem. Soc. 2021, 143, 5616–5621. [44] Ning, X.; Guo, J.; Wolfert, M.-A.; Boons, G.-J. “Visualizing Metabolically Labeled Glycoconjugates of Living Cells by Copper-Free and Fast Huisgen Cycloadditions.” Angew. Chem. Int. Ed. 2008, 47, 2253–2255. [45] Favre, A.; Grugier, J.; Brans, A.; Joris, B.; Marchand-Brynaert, J. “6-Aminopenicillanic acid (6-APA) derivatives equipped with anchoring arms.” Tetrahedron 2012, 68, 10818‒10826. [46] Förster, Th. “Zwischenmolekulare Energiewanderung und Fluoreszenz.” Ann. Physik. 1948, 437, 55‒75. [47] Bernard, V.; Mario, B.-S. Molecular Fluorescence: Principles and Applications, 2nd ed, Weinheim: Wiley-VCH, 2012, pp 213–261. [48] Song, N.; Ding, M.; Pan, Z.; Li, J.; Zhou, L.; Tan, H.; Fu, Q. “Construction of TargetingClickable and Tumor-Cleavable Polyurethane Nanomicelles for Multifunctional Intracellular Drug Delivery.” Biomacromolecules 2013, 14, 4407–4419. [49] Savithri, J.-S.; Rajakumar, P. “Synthesis, Photophysical, and Antioxidant Properties of Rhodamine B Decorated Novel Dendrimers.” Aust. J. Chem. 2018, 71, 399‒406. [50] Wende, C.; Kulak, N. “Fluorophore ATCUN Complexes: Combining Agent and Probe for Oxidative DNA Cleavage.” Chem. Commun. 2015, 51, 12395‒12398. [51] Gottlieb, H.-E.; Kotlyar, V.; Nudelman, A. “NMR Chemical Shifts of Common Laboratory Solvents as Trace Impurities.” J. Org. Chem. 1997, 62, 7512–7515.
指導教授	謝俊結 謝發坤	審核日期	2022-8-12
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