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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77055完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林俊宏(Chun-Hung Lin) | |
| dc.contributor.author | Yu-Ju Peng | en |
| dc.contributor.author | 彭郁茹 | zh_TW |
| dc.date.accessioned | 2021-07-10T21:44:54Z | - |
| dc.date.available | 2021-07-10T21:44:54Z | - |
| dc.date.copyright | 2020-07-17 | |
| dc.date.issued | 2020 | |
| dc.date.submitted | 2020-07-11 | |
| dc.identifier.citation | 1. Sharon, N.; Lis, H., Lectins: Cell-Agglutinating and Sugar-Specific Proteins. Science. 1972, 177 (4053), 949. 2. Sharon, N.; Lis, H., Legume Lectins--a Large Family of Homologous Proteins. FASEB J. 1990, 4 (14), 3198-208. 3. Braakman, I., A Novel Lectin in the Secretory Pathway. EMBO Rep. 2001, 2 (8), 666-668. 4. Roberts, D. L.; Weix, D. J.; Dahms, N. M.; Kim, J. J., Molecular Basis of Lysosomal Enzyme Recognition: Three-Dimensional Structure of the Cation-Dependent Mannose 6-Phosphate Receptor. Cell. 1998, 93 (4), 639-48. 5. Barondes, S. H.; Cooper, D. N.; Gitt, M. A.; Leffler, H., Galectins. Structure and Function of a Large Family of Animal Lectins. J. Biol. Chem. 1994, 269 (33), 20807-10. 6. Crocker, P. R.; Clark, E. A.; Filbin, M.; Gordon, S.; Jones, Y.; Kehrl, J. H.; Kelm, S.; Le Douarin, N.; Powell, L.; Roder, J.; Schnaar, R. L.; Sgroi, D. C.; Stamenkovic, K.; Schauer, R.; Schachner, M.; van den Berg, T. K.; van der Merwe, P. A.; Watt, S. M.; Varki, A., Siglecs: A Family of Sialic-Acid Binding Lectins. Glycobiology. 1998, 8 (2), v. 7. Taylor, M. E., Evolution of a Family of Receptors Containing Multiple C-Type Carbohydrate-Recognition Domains. Glycobiology. 1997, 7 (3), v-viii. 8. Chan, Y. C.; Lin, H. Y.; Tu, Z.; Kuo, Y. H.; Hsu, S. D.; Lin, C. H., Dissecting the Structure-Activity Relationship of Galectin-Ligand Interactions. Int. J. Mol. Sci. 2018, 19 (2). 9. Yang, R. Y.; Rabinovich, G. A.; Liu, F. T., Galectins: Structure, Function and Therapeutic Potential. Expert Rev. Mol. Med. 2008, 10, e17. 10. Konstantinov, K. N.; Robbins, B. A.; Liu, F. T., Galectin-3, a Beta-Galactoside-Binding Animal Lectin, is a Marker of Anaplastic Large-Cell Lymphoma. Am. J. Clin. Pathol. 1996, 148 (1), 25-30. 11. Gao, P.; Simpson, J.; Zhang, J.; Gibson, P., Galectin-3: Its Role in Asthma and Potential as an Anti-Inflammatory Target. Respir. Res. 2013, 14, 136. 12. Dings, R. P. M.; Miller, M. C.; Griffin, R. J.; Mayo, K. H., Galectins as Molecular Targets for Therapeutic Intervention. Int. J. Mol. Sci. 2018, 19 (3), 905. 13. Cao, Z.-Q.; Guo, X.-L., The Role of Galectin-4 in Physiology and Diseases. Protein Cell. 2016, 7 (5), 314-324. 14. Chou, F. C.; Chen, H. Y.; Kuo, C. C.; Sytwu, H. K., Role of Galectins in Tumors and in Clinical Immunotherapy. Int. J. Mol. Sci. 2018, 19 (2). 15. Vasta, G. R., Roles of Galectins in Infection. Nat. Rev. Microbiol. 2009, 7 (6), 424-438. 16. Barondes, S. H.; Castronovo, V.; Cooper, D. N.; Cummings, R. D.; Drickamer, K.; Feizi, T.; Gitt, M. A.; Hirabayashi, J.; Hughes, C.; Kasai, K.; et al., Galectins: A Family of Animal Beta-Galactoside-Binding Lectins. Cell. 1994, 76 (4), 597-8. 17. Cooper, D. N. W., Galectinomics: Finding Themes in Complexity. Biochim. Biophys. Acta. 2002, 1572 (2), 209-231. 18. Hirabayashi, J.; Kasai, K.-i., The Family of Metazoan Metal-Independent β-Galactoside-Binding Lectins: Structure, Function and Molecular Evolution. Glycobiology. 1993, 3 (4), 297-304. 19. Ely, Z. A.; Moon, J. M.; Sliwoski, G. R.; Sangha, A. K.; Shen, X.-X.; Labella, A. L.; Meiler, J.; Capra, J. A.; Rokas, A., The Impact of Natural Selection on the Evolution and Function of Placentally Expressed Galectins. Genome Biol. Evol. 2018, 11 (9), 2574-2592. 20. Hsieh, T.-J.; Lin, H.-Y.; Tu, Z.; Lin, T.-C.; Wu, S.-C.; Tseng, Y.-Y.; Liu, F.-T.; Hsu, S.-T. D.; Lin, C.-H., Dual Thio-Digalactoside-Binding Modes of Human Galectins as the Structural Basis for the Design of Potent and Selective Inhibitors. Sci. Rep. 2016, 6 (1), 29457. 21. Bum-Erdene, K.; Gagarinov, I. A.; Collins, P. M.; Winger, M.; Pearson, A. G.; Wilson, J. C.; Leffler, H.; Nilsson, U. J.; Grice, I. D.; Blanchard, H., Investigation into the Feasibility of Thioditaloside as a Novel Scaffold for Galectin-3-Specific Inhibitors. ChemBioChem. 2013, 14 (11), 1331-42. 22. Zhang, H.; Laaf, D.; Elling, L.; Pieters, R. J., Thiodigalactoside–Bovine Serum Albumin Conjugates as High-Potency Inhibitors of Galectin-3: An Outstanding Example of Multivalent Presentation of Small Molecule Inhibitors. Bioconjugate Chem. 2018, 29 (4), 1266-1275. 23. Hirani, N.; Mackinnon, A.; Nicol, L.; Walker, J.; Ford, P.; Schambye, H.; Pederson, A.; Nilsson, U.; Leffler, H.; Thomas, T.; Francombe, D.; Simpson, J.; Gibbons, M.; Maher, T. M., TD139, A Novel Inhaled Galectin-3 Inhibitor for The Treatment of Idiopathic Pulmonary Fibrosis (IPF). Results from The First in (IPF) Patients Study. QJM-Int. J. Med. 2016, 109 (1), S16. 24. Mohs, R. C.; Greig, N. H., Drug Discovery and Development: Role of Basic Biological Research. Alzheimers. Dement. 2017, 3 (4), 651-657. 25. Sinha, S.; Vohora, D. Pharmaceutical Medicine and Translational Clinical Research; Academic: Boston, 2018; Chapter 2. 26. Szymański, P.; Markowicz, M.; Mikiciuk-Olasik, E., Adaptation of High-Throughput Screening in Drug Discovery-Toxicological Screening Tests. Int. J. Mol. Sci. 2012, 13 (1), 427-452. 27. Mavromoustakos, T.; Durdagi, S.; Koukoulitsa, C.; Simcic, M.; Papadopoulos, M. G.; Hodoscek, M.; Grdadolnik, S. G., Strategies in the Rational Drug Design. Curr. Med. Chem. 2011, 18 (17), 2517-30. 28. Liu, R.; Li, X.; Lam, K. S., Combinatorial Chemistry in Drug Discovery. Curr. Opin. Chem. Biol. 2017, 38, 117-126. 29. Li, Y.; Gabriele, E.; Samain, F.; Favalli, N.; Sladojevich, F.; Scheuermann, J.; Neri, D., Optimized Reaction Conditions for Amide Bond Formation in DNA-Encoded Combinatorial Libraries. ACS Comb. Sci. 2016, 18 (8), 438-443. 30. Nwe, K.; Brechbiel, M., Growing Applications of “Click Chemistry” for Bioconjugation in Contemporary Biomedical Research. Cancer Biother. Radiopharm. 2009, 24, 289-302. 31. Wade, J. V.; Krueger, C. A., Suzuki Cross-Coupling of Solid-Supported Chloropyrimidines with Arylboronic Acids. J. Comb. Chem. 2003, 5 (3), 267-272. 32. Hann, M. M.; Oprea, T. I., Pursuing the Leadlikeness Concept in Pharmaceutical Research. Curr. Opin. Chem. Biol. 2004, 8 (3), 255-263. 33. Caraus, I.; Alsuwailem, A. A.; Nadon, R.; Makarenkov, V., Detecting and Overcoming Systematic Bias in High-Throughput Screening Technologies: A Comprehensive Review of Practical Issues and Methodological Solutions. Brief Bioinform. 2015, 16 (6), 974-986. 34. Enna, S. J.; Bylund, D. B. xPharm: The Comprehensive Pharmacology Reference; Elsevier: New York, 2007; pp 1-7. 35. Rabinovitch, P. S.; Robinson, J. P., Overview of Functional Cell Assays. Curr. Protoc. Cytom. 2002, Chapter 9, Unit 9.1. 36. Parker, G. J.; Law, T. L.; Lenoch, F. J.; Bolger, R. E., Development of High Throughput Screening Assays Using Fluorescence Polarization: Nuclear Receptor-Ligand-Binding and Kinase/Phosphatase Assays. J. Biomol. Screen. 2000, 5 (2), 77-88. 37. Wan, H.; Bergström, F., High Throughput Screening of Drug‐Protein Binding in Drug Discovery. J. Liq. Chromatogr. R. T. 2007, 30 (5-7), 681-700. 38. Wu, B.; Barile, E.; De, S. K.; Wei, J.; Purves, A.; Pellecchia, M., High-Throughput Screening by Nuclear Magnetic Resonance (HTS by NMR) for the Identification of PPIs Antagonists. Curr. Top. Med. Chem. 2015, 15 (20), 2032-2042. 39. Wang, X.; Song, K.; Li, L.; Chen, L., Structure-Based Drug Design Strategies and Challenges. Curr. Top. Med. Chem. 2018, 18. 40. Sliwoski, G.; Kothiwale, S.; Meiler, J.; Lowe, E. W., Jr., Computational Methods in Drug Discovery. Pharmacol. Rev. 2013, 66 (1), 334-395. 41. Wilson, G. L.; Lill, M. A., Integrating Structure-Based and Ligand-Based Approaches for Computational Drug Design. Future Med. Chem. 2011, 3 (6), 735-750. 42. Verlinde, C. L. M. J.; Hol, W. G. J., Structure-Based Drug Design: Progress, Results and Challenges. Structure. 1994, 2 (7), 577-587. 43. Acharya, C.; Coop, A.; Polli, J. E.; Mackerell, A. D., Jr., Recent Advances in Ligand-Based Drug Design: Relevance and Utility of the Conformationally Sampled Pharmacophore Approach. Curr. Comput. Aided Drug Des. 2011, 7 (1), 10-22. 44. Dimakos, V.; Taylor, M. S., Site-Selective Functionalization of Hydroxyl Groups in Carbohydrate Derivatives. Chem. Rev. 2018, 118 (23), 11457-11517. 45. Demizu, Y.; Kubo, Y.; Miyoshi, H.; Maki, T.; Matsumura, Y.; Moriyama, N.; Onomura, O., Regioselective Protection of Sugars Catalyzed by Dimethyltin Dichloride. Org. Lett. 2008, 10 (21), 5075-5077. 46. Saikam, V.; Dara, S.; Yadav, M.; Singh, P. P.; Vishwakarma, R. A., Dimethyltin Dichloride Catalyzed Regioselective Alkylation of cis-1,2-Diols at Room Temperature. J. Org. Chem. 2015, 80 (24), 11916-11925. 47. Uzawa, H.; Minoura, N.; Toba, T.; Nishida, Y.; Kobayashi, K.; Hiratani, K., Convenient Synthetic Approach towards Regioselectively Sulfated Sugars Using Limpet and Abalone Sulfatase-Catalyzed Desulfation. Chem. Commun. 1998, (21), 2311-2312. 48. Christopoulos, T. K.; Diamandis, E. P. Immunoassay; Academic: San Diego, 1996; Chapter 14. 49. Sörme, P.; Kahl-Knutsson, B.; Huflejt, M.; Nilsson, U. J.; Leffler, H., Fluorescence Polarization as an Analytical Tool to Evaluate Galectin–Ligand Interactions. Anal. Biochem. 2004, 334 (1), 36-47. 50. Lowary, T. L.; Hindsgaul, O., Recognition of Synthetic O-Methyl, Epimeric, and Amino Analogues of the Acceptor Alpha-L-Fuc p-(1-->2)-Beta-D-Gal p-OR by the Blood-Group A and B Gene-Specified Glycosyltransferases. Carbohydr. Res. 1994, 251, 33-67. 51. Rossi, A. M.; Taylor, C. W., Analysis of Protein-Ligand Interactions by Fluorescence Polarization. Nat. Protoc. 2011, 6 (3), 365-387. 52. Rajput, V. K.; MacKinnon, A.; Mandal, S.; Collins, P.; Blanchard, H.; Leffler, H.; Sethi, T.; Schambye, H.; Mukhopadhyay, B.; Nilsson, U. J., A Selective Galactose–Coumarin-Derived Galectin-3 Inhibitor Demonstrates Involvement of Galectin-3-glycan Interactions in a Pulmonary Fibrosis Model. J. Med. Chem. 2016, 59 (17), 8141-8147. 53. Hattum, H.; Branderhorst, H.; Moret, E.; Nilsson, U.; Leffler, H.; Pieters, R., Tuning the Preference of Thiodigalactoside- and Lactosamine-Based Ligands to Galectin-3 over Galectin-1. J. Med. Chem. 2013, 56. 54. Delaine, T.; Collins, P.; MacKinnon, A.; Sharma, G.; Stegmayr, J.; Rajput, V. K.; Mandal, S.; Cumpstey, I.; Larumbe, A.; Salameh, B. A.; Kahl-Knutsson, B.; van Hattum, H.; van Scherpenzeel, M.; Pieters, R. J.; Sethi, T.; Schambye, H.; Oredsson, S.; Leffler, H.; Blanchard, H.; Nilsson, U. J., Galectin-3-Binding Glycomimetics that Strongly Reduce Bleomycin-Induced Lung Fibrosis and Modulate Intracellular Glycan Recognition. ChemBioChem. 2016, 17 (18), 1759-1770. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77055 | - |
| dc.description.abstract | 半乳糖凝集素是一種能結合β-半乳糖苷的蛋白，目前發現人類有11種半乳糖凝集素。由於參與多種病理活動，部分半乳糖凝集素被認為是數種疾病的治療標的物，例如乳癌、卵巢癌、心血管疾病以及特發性肺纖維化。然而，因為不同的半乳糖凝集素仍具有高度相似的醣識別區，所以發展具高選擇性的抑制劑是長期必須面臨的挑戰。在這份論文中，我們合成六號脫氧的硫代二半乳糖苷 (deTDG) 衍生物作為半乳糖凝集素的小分子抑制劑，並結合組合化學和結構上的合理設計。其中，我們利用有機錫催化的選擇性醯化和醚鍵生成，在deTDG的三號氫氧基上作衍生。目前已成功鑑定出數種對半乳糖凝集素-3具有良好選擇性及親和力的抑制劑。在這些分子中，選擇性最好的是化合物i，它對半乳糖凝集素-3的親和力比對半乳糖凝集素-1的親和力高54倍。而化合物ii為目前我們發現對半乳糖凝集素-3具有最佳親和力的抑制劑 (Kd = 70 nM)。半乳糖凝集素-1/ii複合體和半乳糖凝集素-3的X射線結構的疊圖中顯示，化合物ii上的羧酸根和半乳糖凝集素-3的精胺酸-144之間存在靜電作用力，進而解釋了其對半乳糖凝集素-3的高親合力。 | zh_TW |
| dc.description.abstract | Galectins represent a class of β-galactoside-binding proteins. There are eleven galectins identified in human. Participating in a variety of pathological activities, several galectin members have been considered as potential therapeutic targets of several diseases, such as breast/ovarian cancer, cardiovascular disease, and idiopathic pulmonary fibrosis. However, the development of highly selective inhibitors is a long-standing challenge since all galectins share a highly similar carbohydrate recognition domain. In this work, we synthesized 6-deoxy thiodigalactoside (deTDG) derivatives as galectin inhibitors and combined the approaches of combinatorial synthesis and structure-based design. Particularly, organotin-catalyzed regioselective acylation or ether formation was established at 3-hydroxyl group of deTDG. Several inhibitors were identified to display satisfying selectivity and affinity for galectin-3. Among them, compound i was the most selective inhibitor, showing 54-fold higher affinity with galectin-3 than with galectin-1. Compound ii was the most potent inhibitor of galectin-3 (Kd = 70 nM). Superimposition of galectin-1/ii and galectin-3 x-ray structures indicated the electrostatic interactions between the carboxylate of compound ii and Arg144 of galectin-3, explaining the extraordinary binding affinity. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-10T21:44:54Z (GMT). No. of bitstreams: 1 U0001-1107202014254500.pdf: 13496528 bytes, checksum: d9c76acccf2d2fe8941a43239272334f (MD5) Previous issue date: 2020 | en |
| dc.description.tableofcontents | 中文摘要 i Abstract ii 目錄 iii 圖目錄 vi 表目錄 viii 流程目錄 ix 簡稱用語對照表 x 中英對照表 xiii 第一章 緒論 1 1-1 半乳糖凝集素 (galectins) 的介紹 1 1-2.1 半乳糖凝集素-3的X-ray結構 3 1-2.2 半乳糖凝集素-3的小分子抑制劑 4 1-2.3 六號脫氧硫代二半乳糖苷 (6-deoxy thiodigalactoside, deTDG) 和半乳糖凝集素-3的結合 4 1-3 小分子藥物的探索與開發 (drug discovery and development) 6 1-3.1 組合化學 (combinatorial chemistry) 6 1-3.2 高通量藥物篩選 (high-throuput screening) 7 1-3.3 合理藥物設計 (rational drug design) 8 1-4 有機錫在醣類上的選擇性化學 9 第二章 實驗目標與設計 11 2-1 實驗目標 11 2-2 實驗設計 11 2-2.1 六號脫氧硫代二半乳糖苷作為母核的設計 12 2-2.2 利用有機錫的選擇性化學快速建立小分子庫 (compound library) 13 2-2.3 偏極化螢光法 (fluorescence polarization, FP) 的快速篩選應用 13 2-2.4 合理引入負電荷基團來提升抑制劑的選擇性 14 第三章 結果與討論 16 3-1 deTDG的合成 16 3-1.1 deTDG_E的合成 17 3-1.2 deTDG_B的合成 19 3-2 deTDG酯類衍生物的小分子庫建立及快速篩選結果 20 3-2.1 小分子庫的建立及篩選的初步結果 20 3-2.2 deTDG酯類衍生物的合成 23 3-2.3 deTDG酯類衍生物的結合力 24 3-2.4 片段設計 (fragment-based design) deTDG衍生物的合成及結合力 27 3-2.5 deTDG酯類衍生物的穩定性 30 3-3 deTDG醚類衍生物引入負電荷基團的理性設計結果 32 3-3.1 deTDG醚類衍生物引入負電荷基團的合成 32 3-3.2 deTDG醚類衍生物引入負電荷基團的結合力 34 3-4 半乳糖凝集素和deTDG衍生物的晶體結構 38 3-5 對半乳糖凝集素-3具高選擇性deTDG衍生物的細胞實驗 43 3-6 結論 46 3-7 未來展望 47 第四章 實驗方法 51 4-1 General Methods and Instrumentation 51 4-2 Synthesis and Characterization of Compounds 52 4-3 General procedure for regioselective acylations and in situ screening 102 4-4 Isothermal titration calorimetry (ITC) experiments to determine binding affinity and related thermodynamic parameters 103 4-5 Fluorescence polarization (FP) experiments to determine binding affinity 104 4-5 Stability test by NMR experiments 107 References 108 Appendix I 1H/13C NMR Spectra of Compound 116 Appendix II 19F/2D NMR Spectra of Compound 149 Appendix III FP assay data 164 Appendix IV ITC data 171 | |
| dc.language.iso | zh-TW | |
| dc.subject | 抑制劑 | zh_TW |
| dc.subject | 半乳糖凝集素-3 | zh_TW |
| dc.subject | X射線結晶學 | zh_TW |
| dc.subject | 等溫量熱滴定法 | zh_TW |
| dc.subject | 有機錫 | zh_TW |
| dc.subject | 組合化學 | zh_TW |
| dc.subject | isothermal titration calorimetry | en |
| dc.subject | inhibitor | en |
| dc.subject | X-ray crystallography | en |
| dc.subject | Galectin-3 | en |
| dc.subject | organotin | en |
| dc.subject | combinatorial chemistry | en |
| dc.title | "合成3,3'-雙取代的六號脫氧硫代二半乳糖苷作為具選擇性的半乳糖凝集素-3抑制劑" | zh_TW |
| dc.title | Synthesis of 3,3'-disubstituted 6-deoxy thiodigalactosides as selective galectin-3 inhibitors | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 108-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.author-orcid | 0000-0001-7352-5746 | |
| dc.contributor.advisor-orcid | 林俊宏(0000-0002-6795-8825) | |
| dc.contributor.oralexamcommittee | 劉扶東(Fu-Tong Liu),方俊民(Jim-Min Fang),梁博煌(Liang-Po Huang),徐尚德(Shang-Te Danny Hsu) | |
| dc.contributor.oralexamcommittee-orcid | 劉扶東(0000-0002-3354-1001),方俊民(0000-0002-6070-3408),梁博煌(0000-0003-1207-5256),徐尚德(0000-0002-7231-0185) | |
| dc.subject.keyword | 半乳糖凝集素-3,抑制劑,組合化學,有機錫,等溫量熱滴定法,X射線結晶學, | zh_TW |
| dc.subject.keyword | Galectin-3,inhibitor,combinatorial chemistry,organotin,isothermal titration calorimetry,X-ray crystallography, | en |
| dc.relation.page | 200 | |
| dc.identifier.doi | 10.6342/NTU202001439 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2020-07-13 | |
| dc.contributor.author-college | 理學院 | zh_TW |
| dc.contributor.author-dept | 化學研究所 | zh_TW |
| 顯示於系所單位： | 化學系 | |
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