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開發小分子藥物用於治療中樞神經系統疾病

為了解決SHOEI usa的問題，作者曾惠如 這樣論述：

Table of Contents摘要 1Abstract 2I Protein disulfide isomerase-4 inhibitors against glioblastoma: design, synthesis and biological evaluation 3A. Introduction 41. Introduction of glioblastoma 42. Introduction of protein disulfide isomerase 83. Relationship between PDI and cancer 144. Res

earch object and design 16B. Result and Discussion 201. Chemistry 202. Biological evaluation and docking analysis 25C. Conclusion 34II Acridine-based histone deacetylase inhibitors as multitarget agents against Alzheimer’s disease: synthesis and biological evaluation 35A. Introduction 3

61. Introduction of Alzheimer’s disease 362. Current therapeutic options and benefit of multitarget agents 383. Introduction of histone deacetylase 394. Relationship between HDAC and AD 415. Introduction of beta amyloid and its relationship with AD 436. Introduction of acetylcholinesteras

e and its relationship with AD 467. Research purpose and design 48B. Result and Discussion 501. Chemistry 502. Biological evaluation and docking analysis 53C. Conclusion 72III Sobrerol derivatives against autoimmune neurologic disease: synthesis and biological evaluation 73A. Introduct

ion 741. Introduction of multiple sclerosis 742. Current therapeutic options and unmet medical need 773. Introduction of interleukin-6 804. Relationship between interleukin-6 and multiple sclerosis 835. Research purpose and design 85B. Result and Discussion 861. Chemistry 862. Biolog

ical evaluation 87C. Conclusion 91Experimental Section 92I. Machine and material 921. General machines and methods: 922. Materials and solvents purchased from: 923. Purification and dehydration of solvent: 95II. Chemistry synthetic routes and physical properties 96A. Protein disulfide

isomerase-4 inhibitors against glioblastoma: design, synthesis and biological evaluation 96B. Acridine-based histone deacetylase inhibitors as multitarget agents against Alzheimer’s disease: synthesis and biological evaluation 128C. Sobrerol derivatives against autoimmune neurologic disease: sy

nthesis and biological evaluation 137III. Method of biological assay 146A. Protein disulfide isomerase-4 inhibitors against glioblastoma: design, synthesis and biological evaluation 146B. Acridine-based histone deacetylase inhibitors as multitarget agents against Alzheimer’s disease: synthesis

and biological evaluation 148C. Sobrerol derivatives against autoimmune neurologic disease: synthesis and biological evaluation 154Reference 155Supplementary Figures 176List of TablesTable 1. The human PDI family. 10Table 2. IC50 value for the inhibition against PDIA4 by compounds 5b-c 25Tab

le 3. IC50 value for the inhibition against PDIA4 by compounds 11a-c 28Table 4. IC50 value for the inhibition against PDIA4 by compounds 23a-v 29Table 5. Cytotoxicity of PDIA4 inhibitors in glioblastoma cell line, U-87 MG 31Table 6. PAMPA-BBB results of compound 23v and reference compounds 32Tab

le 7. Four stages of Alzheimer’s disease as well as related symptoms. 37Table 8. The human HDAC family. Classes, HDACs, subcellular localization, and structures of HDAC isoforms. 40Table 9. IC50 value (μM) of compounds 31a-d against HDACs. 53Table 10. IC50 value (μM) of compounds 36a-h against HD

ACs 55Table 11. Inhibitory activities of compounds 31a, and 36a-h against Aβ1-42 oligomerization 57Table 12. IC50 value (μM) of compounds 31a, and 36a-h against AChE 58Table 13. IC50 value (μM) of compounds 31a, and 36b against HDAC1, -2, and -3. 59Table 14. EC50 value for increasing acetylation

of histone H3 and tubulin by quantification of western blot. 66Table 15. Metabolic stability of compounds 31a, 36b, and testosterone 69Table 16. BBB permeability evaluation of compounds 31a, and 36b using MDR1-MDCK permeability model 70Table 17. Clinical used disease-modifying therapies of MS 7

8Table 18. Classification of immune-related cytokines. 80Table 19. Cytokines and their functions. 82Table 20. IC50 of sobrerol derivatives in inhibiting IL-6 expression. 89List of FiguresFigure 1. WHO 2016 classification of diffuse gliomas 5Figure 2. FDA approved anti-glioma agents in chemothera

py 7Figure 3. Illustration of disulfide bonds formation and redox reactions involving PDI. 8Figure 4. Schematic overview of PDI structure. 9Figure 5. Schematic overview of relationship between ER stress, UPR, and PDI in cancer cell. 15Figure 6. Chemical structure of reported PDI inhibitors. 17F

igure 7. Flowchart of the process for lead-compound identification. 18Figure 8. Design of potent PDIA4 inhibitors. 19Figure 9. Molecular docking and interaction analysis of compounds 5b and 5c.. 27Figure 10. Molecular docking and interaction analysis of compound 23v. 30Figure 11. Anticancer acti

vities of compound 23v in human glioblastoma U-87 MG xenograft mouse model 33Figure 12. FDA approved drugs in treating AD patients. 38Figure 13. Tau incorporate with HDAC6 to form pathological tau beading. 42Figure 14. Molecular mechanisms of Aβ-oligomers synaptotoxicity 43Figure 15. Graphic ill

ustration of amyloid precursor protein (APP) metabolism 44Figure 16. Graphic illustration of biological action of acetylcholine. 47Figure 17. Reported anti-AD agents with acridine-related structures. 48Figure 18. Reported HDAC inhibitor. 49Figure 19. Design of a novel series of multi-target drug

s for AD treatment. 49Figure 20. Illustration of inhibiting assay of Aβ1-42 oligomerization. 56Figure 21. Illustration of inhibiting assay of Aβ1-42 oligomerization. 56Figure 22. Validation of docking protocol 60Figure 23. Docking pose and interaction of compounds 31a and 36b 61Figure 24. Docki

ng pose and interaction of compound 31a in HDAC6 and HDAC7. 62Figure 25. Docking poses and interactions of compounds 31a and 36b 64Figure 26. Western blot analysis of compounds 31a and 36b in murine neuroblastoma N2a cells 65Figure 27. Graphic illustration of cell viability of compounds 31a and 3

6b 66Figure 28. Enhancement of primary rat hippocampal neurite outgrowth by compounds 31a and 36b 67Figure 29. Quantification of lengths and numbers of primary rat hippocampal neurite branching 68Figure 30. Nesting behavior of APP/PS1 mice treated with compounds 31a and 36b 71Figure 31. Cost of

multiple sclerosis and according economic burden 74Figure 32. Graphic illustration of four categories of multiple sclerosis. 76Figure 33. examples of disease-modifying agents of multiple sclerosis. 79Figure 34. Biological function of interleukin-6 in inflammation, immune, and disease 81Figure 35

. Potential roles of IL-6 in autoimmune neurological disease 84Figure 36. Design strategy of IL-6 secretion inhibitors. 85Figure 37. Bar figure illustration of inhibitory activity of sobrerol derivatives against IL-6 expression 87Figure 38. Structure-activity relationship of sobrerol derivatives.

88Figure 39. Bar figure illustration of cytotoxicity of sobrerol derivatives 90List of SchemesScheme 1. Synthetic route of compounds 5a-c. 21Scheme 2. Synthetic route of compounds 11a-c. 22Scheme 3. Synthetic route of compound 19. 23Scheme 4. Synthetic route of compounds 23a-v. 24Scheme 5. Sy

nthetic route of compounds 31a-d. 50Scheme 6. Synthetic route of compounds 36a-h. 52Scheme 7. Synthetic rout of compounds 38a-r. 86Scheme 8. Synthetic rout of compounds 39. 86

混合車流下圓環儀控方法研究

為了解決SHOEI usa的問題，作者許晟松 這樣論述：

由於圓環(Roundabout)的在路口中特性為兼具安全及在中低流量下的紓解效率高，因此一直以來流行於歐洲國家。而近年來，美國朝向道路節食(Road diet)及開始增設圓環的方向發展、日本也開始推廣無號誌圓環路口。可見圓環路口是現代交通工程的發展趨勢。然而，台灣的都會區交通具有相當高的汽機車混合比及私人運具旅次佔比，不利於圓環的發展。本研究針對尖峰車流特性明顯之路口來設置儀控圓環，希望能夠透過儀控的方式來增加圓環的整體容量，並且在一般時間處於無號誌圓環狀態，減少設置為號誌路口的延滯浪費，一併解決延滯及路口安全問題。拓展無號誌圓環相對於號誌路口的可適用性，提升將路口設計為圓環的誘因。本研究探

討在尖峰時間不平衡車流的條件下，透過佔有率法進行演算，並且以VisVAP 來撰寫圓環儀控策略，在不過度影響幹道車流的前提下，提供幹道車流下游受影響車輛足夠的時間間距進入圓環，降低延滯及排隊長度，增加整體的紓解效率。本研究亦討論適合的最小空白時間及最小儀控時間，做為降低對幹道車流的影響及增加支道車流紓解量兩者之間的取捨探討。藉由嚴格的模型校估驗證後，來證明此模擬法具有可信度，再進行多種不同的需求比、轉向比及混合比情境分析，以及儀控圓環、無號誌圓環及一般號誌十字路口模擬比較。透過類似於佔有率匝道儀控法的模型，本研究分析各種情境下的平均每車延滯及最大排隊長度的績效結果，發現相對於無號誌圓環此圓環儀控

不管在任何混合比皆能夠在僅些微影響幹道車流延滯的條件下大幅降低支道車流及整體路口的延滯，因而降低號誌路口設計為圓環的門檻。