生物分子、硫醇和抗瘧藥物對於β-血紅素的生物礦化動力學之影響

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研究生：	蔡旻翰 Ming-Han Tsai
論文名稱：	生物分子、硫醇和抗瘧藥物對於β-血紅素的生物礦化動力學之影響 The Effects of Biogenic Molecules, Thiol and Antimalarial Drugs on Biocrystallization Kinetics of β-Hematin Formation
指導教授：	李度 Tu Lee
口試委員:
學位類別：	碩士 Master
系所名稱：	工學院 - 化學工程與材料工程學系 Department of Chemical & Materials Engineering
畢業學年度：	99
語文別：	英文
論文頁數：	168
中文關鍵詞：	結晶、瘧疾、硫醇、抗瘧藥物、血紅素、生物礦化、動力學、生物分子
外文關鍵詞：	biocrystallization, hematin, antimalarial drugs, thiol drugs, biogenic molecules, kinetics, malaria, crystal
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大約有40%的世界人口正處於可能遭受瘧疾感染的威脅。根據最新的統計，每年約有百餘萬的臨床病例並造成約80萬的死亡人數。瘧疾是由瘧原蟲所引起的，其中惡性瘧原蟲是造成死亡人數最多的一種瘧原蟲。雖然目前抗瘧疾藥物的治療效果良好，但是人與瘧疾的戰爭尚未結束，因為這些藥物廣泛的使用，造成了瘧疾對這些藥物逐漸產生抗藥性，所以有必要篩選及發展新的抗瘧疾藥物。目前有五種治療瘧疾的目標類型，我們著重於干擾其中hemozoin（β-hematin，其組成為ferriprotoporphyrin IX（Fe(III)PPIX））的生物結晶過程。在此論文中，我們不僅修飾了抗瘧疾藥物的篩選方法和成功的發現一種疑似可行的新藥物組合，並整合了hemozoin的生物結晶反應機制，也發現由不具催化效益的脂質（palmitic acid）和具有催化效益的脂質（1,2-dioleoyl-sn-gylcero-3-phosphocholine）混合後的脂質性質的重要性。

About 40% of the world’s population lives in a threat from malaria infection. According to the current statistics, there were more than hundred millions of clinical cases and 800,000 deaths each year. Malaria was caused by Plasmodium parasites, which Plasmodium falciparum was one of the Plasmodium parasites that caused the most death in the world. Although the present antimalarial drugs worked well in treatments, the war against malaria was not over yet. Drug resistance began to develop due to the widely used of antimalarial drugs. Therefore, it is necessary to screen and develop new antimalarial drugs. There were five types of drug targets in malaria treatment, and we focused on interfering the biocrystallization process of hemozoin, also called β-hematin, formation (consists of ferriprotoporphyrin, Fe(III)PPIX). In this work, we not only modified the drug screening method for antimalarials and successfully developed a plausible drug combination to fight against malaria, but also mapped out the reaction mechanism for biocrystallization of hemozoin and discovered the importance of the lipid blends upon an active promoter (1,2-dioleoyl-sn-gylcero-3-phosphocholine) and an inactive promoter (palmitic acid).

摘要	i
Abstract	ii
Acknowledgement	iii
Table of Contents	iv
List of Tables	viii
List of Figures	ix
Chapter 1 Executive Summary	1
1.1 Introduction	1
1.2 History of Malaria	1
1.3 Life Cycle of Plasmodium falciparum	3
1.4 Currently Used Antimalarials	4
1.5 Conceptual Framework	7
1.6 References	9
Chapter 2 The Crystallization Mechanism and the Relationship between Hemozoin and β-Hematin	12
2.1 Introduction	12
2.2 The Characterizations of in vitro vs. in vivo	17
2.3 The Mechanisms of Hemozoin and β-Hematin Formation	21
2.3.1 Hemozoin Formation	21
2.3.2 β-Hematin Formation	23
2.4 The Recent Drug Screening Methods (in vitro)	26
2.5 The Instrumentation Methods for the Kinetic Studies on β-Hematin Formation (in vitro)	30
2.5.1 The FT-IR Method	30
2.5.2 The UV/vis Solid Method	31
2.5.3 The UV/vis Solution Method	32
2.6 Conclusions	33
2.7 References	34
Chapter 3 The Fundamental Properties of Hematin and β-Hematin	48
3.1 Introduction	48
3.2 Materials	49
3.3 Solvents	51
3.4 Experimental Procedures for Solubility Determination	54
3.5 Experimental Procedures for Solvent Screening of β-Hematin Formation	55
3.6 The Solubility of Hematin and Synthesized β-Hematin	56
3.7 Results and Discussion of Modified Solvent Screening Method	57
3.8 Conclusions	64
3.9 References	65
Chapter 4 The Effect of Biogenic Molecules, Thiol and Antimalarial Drugs on Biocrystallization Kinetics of β-Hematin Formation	67
4.1 Modified Rapid Screening (High-Throughput Screening)	67
4.2.1 Materials, Solvents, Solutions and Experimental Methods	70
4.2.2 Analytical Measurements	75
4.2.3 Results and Discussion	76
4.2.4 Conclusion	85
4.3 Kinetic Studies on β-Hematin Formation	87
4.3.1 Materials and Experimental Methods	88
4.3.2 Analytical Measurements	94
4.3.3 Results and Discussion	95
4.3.4 Conclusions	105
References	107
Chapter 5 Conclusions and Future Works	114
5.1 Newly Modified Rapid Screening Technique	114
5.2 Kinetic Studies of β-Hematin Formation	114
A.1 Introduction	116
A.2 Solution Phase	119
A.2.1 Ultraviolet-Visible Molecular Absorption Spectrometer (UV/vis)	119
A.3 Solid Phase	123
A.3.1 Powder X-ray Diffraction (PXRD)	123
A.3.2 Fourier Transform Infrared (FT-IR) Spectroscopy	126
A.3.3 Low Vacuum Scanning Electron Microscopy (LV-SEM)	129
A.4 Lipid Characterization	133
A.4.1 Low Temperature Differential Scanning Calorimetry (LT-DSC)	133
A.5 Conclusions	136
A.6 References	137
Appendix B List of Chemical Structures	142
Appendix C Supporting Information	144

                                

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