博碩士論文 105223018 詳細資訊



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姓名 高樂(Le Kao)  查詢紙本館藏   畢業系所 化學學系
論文名稱 LCA-Fentanyl Hybrid Molecules: Anaesthetic Implications of Antimetastasis Chemotherapy
(LCA-Fentanyl Hybrid Molecules: Anaesthetic Implications of Antimetastasis Chemotherapy)
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摘要(中) 第一章節

過敏性休克是一種不常見但發作有危及性命可能的全身性過敏。常見的過敏原有三: 食物、藥物及昆蟲。台灣近十年來，由藥物造成的過敏案例逐漸上升，而在藥物造成的過敏中，非類固醇抗發炎藥物、麻醉劑、抗生素為常見的過敏原。相較於另外兩種藥物造成的過敏，麻醉劑造成的過敏特別難診斷及確定何為確切過敏原，因為病人於手術期接觸到的不只是麻醉劑，可能有抗發炎藥物、導引劑等等…。又進行手術中時，時常使用數種麻醉劑於病患身上，而這讓其診斷變得更加困難。過敏反應依據機制不同分為四類，過敏性休克被認為是由抗體IgE介導的第一型過敏反應，然而過敏性休克完整的機制尚未完全明瞭。
根據林口長庚醫院近年來的病例統計以及其實驗室進行的in vitro實驗結果，fentanyl是常見可能致敏的麻醉藥之一。以現有的實驗檢測並不能確定其是否是致敏藥常見的方法有比較inflammatory mediators增加的數量，然而其結果並不能作為過敏反應的指標，因為造成mediators增加的原因並不完全來自過敏原。除此之外，看嗜鹼性白血球活化的比例也是方法之一，不過他的sensitivity不高，故也有誤判的可能。因此，鐘文宏博士希望將目標放在機制上游的B細胞受體上。為了進行此實驗，我們和鐘醫師實驗室合作，負責合成一系列Fentanul衍生物。
我們合成出FA04、FC04、FA22、FC22。以實驗結果看來，FA04、FC04、FA22、FC22對某些病患有mediators增加、嗜鹼性白血球明顯活化、B細胞及漿細胞數量增多的現象。
 

第二章節

癌症一直是難以治癒的疾病，然而透過抽絲剝繭的方式，科學家也找出一些與癌症有重要關聯的物質，在人體內第二重要的醣類: 唾液酸(Sialic acids)即是之一。科學家發現相較於正常細胞，惡性腫瘤常常在細胞表面有過多的唾液酸，且其參與許多癌細胞的發展過程。唾液酸一般出現在細胞表面的多醣分子(Glycan)鏈末端，將唾液酸加到鏈上的反應稱為唾液酸化(Sialylation)，由唾液酸轉移酶(Sialyltransferase)調控此反應，透過抑制唾液酸轉移酶可以作為可能的癌症治療藥物。
本實驗室一直致力發展唾液酸轉移酶抑制劑(Sialyltransferase inhibitors)，過去已找出對於唾液酸轉移酶具有明顯抑制效果由石膽酸(Lithocholic acid)衍生的Lith-O-Asp。此次，我們看好Fentanyl的免疫調節效果，將Fentanyl和Lith-O-Asp結合在一起合成出KL03、KL04、KL05、KL06、KL08
我們發現KL05及KL04對於乳癌細胞MDA-MB-231有毒殺效果，且有抑制其轉移的作用，然而抑制轉移的效果可能來自於其對細胞的毒性。未來我們將比較其對於正常細胞的毒性以期發現KL05及KL04的毒性是否有價值。
摘要(英) Chapter I

Anaphylaxis is a rare but severe allergic reaction, which has rapid onset and may put patients’ life in danger. Most common causes of anaphylaxis are food, medicines and insects. Antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs) and anesthetics are the three most common causes of anaphylaxis among other medicines. Compares with the other common causes of drug-induced anaphylaxis, the diagnosis of anesthetic-induced anaphylaxis is way difficult, because that the patients used multiple drugs not only anesthetics but also induction agents during the perioperative period, which does not make the diagnosis of anesthetics hypersensitivity reaction to be as obvious as the one of other drug-induced hypersensitivity reaction. Anaphylaxis is considered to be a type I hypersensitivity reaction mediated by IgE. Hypersensitivity reactions are classified into four types. However, the detailed mechanism of anaphylaxis is still unclear. The existing in vitro tests for type I hypersensitivity, their sensitivity and specificity are poor to make the misjudgment plausible. For reasons outlined above, we cooperated with Wen-Hung Chung, M.D., Ph.D. in the study; we synthesized the analogues of fentanyl.
We synthesized FA04, FC04, FA22 and FC22. The results of in vitro tests showed that they could lead the increasing IgE, activated basophils, b cells and plasma cells. The calculation for the ratio of activated B cells is in progress, the results will reveal whether the activated B cells were truly cause by fentanyl derivatives.
 

Chapter II

Cancer has been a refractory disease, scientists sill found some molecules that are highly relative to cancer, and one of them is sialic acid. They also found that metastatic cancer cells have the property of expressing plenty of glycoproteins with numerous sialic acids to the terminal position on the surface. Sialic acid participated in tumor progressions. Sialylation is the attachment process of sialic acid onto other molecules, and it is mediated by sialyltransferases (STs). Sialyltransferases inhibitors may be a therapeutic treatment for cancer.
Our lab has been developing sialyltransferases inhibitors, and we have found a good sialyltransferases inhibitors based on lithocholic acids which is Lith-O-Asp. Now, we put expect on the immunomodulatory effect of fentanyl to create a series fentanyl/lithocholic acid analogs: KL03, KL04, KL05, KL06 and KL08.
We found that KL05 and KL04 have cytotoxicity and inhibition in MDA-MB-231 cells, but the inhibition may be due to their cytotoxicity. Thus, we are going to test their cytotoxicity in the normal cells to compare the result in MDA-MB-231 cells.
關鍵字(中) ★ 芬太尼
★ 石膽酸
★ 唾液酸轉移酶抑制劑
★ 過敏性休克		 關鍵字(英) ★ Fentanyl
★ Lithocholic acid
★ Sialyltransferase inhibitors
★ Anaphylaxis
論文目次 摘要 I
Abstract ІІІ
誌謝 V
Table of Contents VІ
List of Figures VІІІ
List of Tables IX
List of Schemes X
Abbreviations XI
Chapter I
1. Introduction 1
1.1 Research Background Information 1
1.2 Pathophysiology of type I hypersensitivity 2
1.3 B cell receptors 4
1.4 Anesthetic-induced anaphylaxis 5
2. Result and Discussion 7
2.1 Research motivation 7
2.2 Synthesis of Fentanyl derivatives 8
2.2.1 Synthesis of Fentanyl 8
2.2.2 Synthesis of FA22 9
2.2.3 Synthesis of FC22 10
2.2.4 Synthesis of FA04 11
2.2.5 Synthesis of FC04 12
2.3 In vitro study of FA22, FC22, FA04 and FC04 13
2.3.1 Drug-specific immunoglobulins ELISA 13
2.3.2 Basophil activation test 14
2.3.3 B cell culture test 15
2.4 Conclusion 19
3. Methodology 20
3.1 General Information 20
3.2 Experimental Section 20
3.2.1 Preparation of Fentanyl 20
3.2.2 Preparation of FA22 22
3.2.3 Preparation of FC22 24
3.2.4 Preparation of FA04 27
3.2.5 Preparation of FC04 28
4. Spectrum 29
5. Reference 45
Chapter II
1. Introduction 49
1.1 Research Background Information 49
1.2 Sialic acid 51
1.3 Sialyltransferase and sialylation in cancer 53
1.4 Sialyltransferase inhibitors 54
1.4.1 Lithocholic acid derivatives as sialyltransferase inhibitors 55
1.5 Bisubstrate inhibitors to sialyltransferases: fentanyl and Lith-O-Asp 56
2. Result and Discussion 58
2.1 Research motivation 58
2.2 Synthesis of bisubstrate compounds of fentanyl and Lith-O-Asp 61
2.2.1 Synthesis of FC22-2, KL05, KL03 and KL04 61
2.2.2 Synthesis of FC23, KL06 and KL08 63
2.3 In vitro study of KL03, KL04 and KL05 66
2.3.1 Cytotoxicity of compounds in MDA-MB-231 cells 66
2.3.2 Effect of compounds on migration in MDA-MB-231 cells 67
2.4 Conclusion 69
3. Methodology 70
3.1 General Information 70
3.2 Experimental Section 71
3.2.1 Preparation of FC22-2 71
3.2.2 Preparation of KL05 73
3.2.3 Preparation of KL03 74
3.2.4 Preparation of KL04 76
3.2.5 Preparation of FC23 78
3.2.6 Preparation of KL06 80
3.2.7 Preparation of KL08 82
4. Future works 84
5. Spectrum 85
6. Reference 104
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指導教授 李文山 李文仁 審核日期 2018-9-20
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