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研究生:許瑋心
研究生(外文):Wei-Hsin Hsu
論文名稱:設計與合成醣磷酸和膦酸衍生物來抑制結核麥芽糖基轉移酶
論文名稱(外文):Design and Synthesis of Sugar Phosphates and Phosphonates for Inhibition of Tuberculosis Maltosyltransferase
指導教授:方俊民方俊民引用關係
指導教授(外文):Jim-Min Fang
口試日期:2017-07-24
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:化學研究所
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:英文
論文頁數:219
中文關鍵詞:肺結核抑制劑
外文關鍵詞:TuberculosisInhibition
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現在所流行的肺結核中,多數是結核分支桿菌所感染。多重抗藥性與廣泛性抗藥性的肺結核在全球造成嚴重的病情。在2015年間,共有一千萬新的肺結核病例被報導,在其中約有五十萬個病例為多重抗藥性的病例。現行有些多重抗藥性的藥物與治療方法在積極使用中,但針對廣泛性抗藥性肺結核的治療仍有其瓶頸與限制。因此,針對新標的蛋白質的新型肺結核藥物的開發勢在必行。本研究擬開發新型的肺結核藥物,主要的概念為模擬結核分支菌內所具備的重要酵素GlgE的受質,麥芽糖-1-磷酸(maltose-1-phosphate),來設計抑制劑。GlgE是結核分支菌由海藻醣生成α-葡聚醣的四步驟合成途徑的一環,若是有效抑制GlgE轉醣酶,並促使受質麥芽糖-1-磷酸的堆積,可引發結核分支菌內自體中毒的效果,有效殺死細菌。但目前尚且無有效的GlgE抑制劑,因此我們設計一些潛在的GlgE抑制劑將更能了解麥芽糖轉醣酶的藥理機制。

在我們的設計中預期合成醣磷酸與膦酸衍生物16與18作為針對肺結核桿菌GlgE抑制劑。我們嘗試運用烯丙基、第三丁基二甲基矽基與乙醯基等保護基進行研究路徑的研究,期望得到目標產物醣磷酸衍生物16。我們成功的合成出乙醯基保護的中間體57,並得到苯基與三氯乙基保護的磷酸酯衍生物58與59,最後利用磷酸酯衍生物59去保護成功地得到磷酸衍生物16。另外,在醣膦酸衍生物18的合成上,我們也嘗試了乙醯基、苄醯基與第三丁基二甲基矽基等不同的保護基。從縮醛化合物34,我們得到3,6-第三丁基二甲基矽基取代的葡萄糖衍生物90。嘗試利用90進行威悌反應,然而反應結果仍不如預期。最終,我們提出一條新的合成路徑不需要經過威悌反應期望能得到目標化合物18。
Tuberculosis, a disease caused by bacterial pathogens Mycobacterium tuberculosis, was regarded as under control in the past decades. However, the multi-drug-resistant tuberculosis (MDR-TB) and extensively-drug-resistant tuberculosis (XDR-TB) have emerged to become a serious global health crisis. In 2015, there were an estimated 10.4 million new TB cases worldwide, including nearly a half million cases of MDR-TB. Although there are anti-MDR-TB drugs, it is still needed to develop new drugs targeting different TB proteins for treatment of the XDR-TB patients.
GlgE is a maltosyltransferase that uses maltose-1-phosphate as the substrate. GlgE involves in a four-step pathway for the production of α-glucan from trehalose, an essential process for mycobacterial survival. Inhibition of GlgE causes accumulation of maltose-1-phosphate, and triggers the self-poisoning of M. tuberculosis. According to the toxic effect and synthetic lethal pathway, GlgE becomes an appealing drug target. As no effective GlgE inhibitor has been discovered, we thus designed some potential GlgE inhibitors by mimicking the structure of maltose-1-phosphate, the GlgE substrate.

Our initial aim is to synthesize the sugar phosphate and phosphonate compounds 16 and 18 as GlgE inhibitors against M. tuberculosis. We have searched several approaches to synthesize the D-glucosyl phosphate 16 by using allyl, TBDMS and acetyl protecting groups. The acetyl protected intermediate 57 was successfully synthesized from D-glucose as the starting material. We also converted compound 57 to phosphate esters 58 and 59 with phenyl and trichloroethyl as the R groups, respectively. The sugar phosphate 16 was finally achieved by two steps of deprotection from phosphate ester 59.
Various protecting groups, including the acetyl, benzoyl and TBDMS groups, have been used in the synthetic approach to compound 18. We have prepared the 3,6-TBS protected glucose 90 from acetal 34. Nevertheless, Wittig reaction of compound 90 still failed. We propose another novel approach to compound 18 without using Wittig reaction.
Chinese Abstract I
English Abstract II
Table of Contents IV
List of Figures VII
List of Tables VIII
List of Schemes IX
Abbreviation X
Chapter 1. Introduction 1
1.1 History of tuberculosis 1
1.2 Tuberculosis in modern era 2
1.3 The genus of Mycobacterium 3
1.4 Current treatment of TB and rise of MDR and XDR strains 4
1.5 Pathology and immunology of M. tuberculosis infection 7
1.5.1 Phagocytosis of M. tuberculosis by macrophages 8
1.5.2 Development of tuberculosis granuloma 9
1.5.3 Survival of M. tuberculosis inside macrophages 10
1.6 Mycobacterial cell envelope 12
1.6.1 Cell wall core and mAGP complex 13
1.6.2 Capsular layer 14
1.7 α-D-Glucan 16
1.7.1 Rv3032 pathway 18
1.7.2 GlgE pathway 20
1.8 Maltosyltransferase GlgE 22
1.8.1 Structure of GlgE 23
1.8.2 Catalysis mechanism of GlgE 25
1.8.3 Drug candidate for TB treatment 26
1.9 Recent investigations of potential GlgE inhibitors 28
1.9.1 Structural comparison of M. tuberculosis GlgE and S. coelicolor GlgEI 28
1.9.2 GlgE inhibitors 29
Chapter 2. Results and Discussion 32
2.1 Design of GlgE inhibitors 32
2.2 Synthesis of GlgE inhibitors 33
2.2.1 Proposed synthetic scheme of glucopyranosyl phosphate 34
2.2.2 Proposed synthetic scheme of C-glycoside phosphonate 36
2.3 Synthesis of unsubstituted sugar phosphate 16 37
2.3.1 Synthesis of allyl-protected benzyl-α-D-glucopyranosyl phosphate derivative 37
2.3.2 Synthesis of tert-butyldimethylsilyl-protected benzyl-α-D-glucopyranosyl phosphate derivative 46
2.3.3 Synthesis of acetate-protecting benzyl-α-D-glucopyranosyl phosphate derivative 48
2.4 Synthesis of 4-O-trihydroxybenzyl-α-D-glucopyranosyl phosphate derivative 17 54
2.4.1 Synthesis of allyl-protected sugar phosphate derivatives 54
2.4.2 Synthesis of tert-butyldimethylsilyl-protected sugar phosphate derivatives 56
2.4.3 Synthesis of ester-protected sugar phosphate derivatives 58
2.5 Synthesis of 4-O-benzyl-α-D-glucopyranosyl phosphonate derivative 18 62
2.5.1 Synthesis of acetyl-protected 4-O-benzyl-α-D-glucopyranosyl phosphonate 62
2.5.2 Attempted Wittig reaction with benzoyl protecting group 62
2.5.3 Synthesis of tert-butyldimethylsily-protected α-D-glucopyranosyl phosphonate 63
Chapter 3. Conclusion and Perspective 66
Chapter 4. Experimental Section 71
4.1 General description 71
4.2 Synthetic procedures and characterization of compounds 72
Bibliography 126
APPENDIX. Nuclear Magnetic Resonance Spectra 136
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