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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 方俊民 | |
| dc.contributor.author | Ling-Wei Li | en |
| dc.contributor.author | 李苓瑋 | zh_TW |
| dc.date.accessioned | 2021-06-16T02:28:37Z | - |
| dc.date.available | 2020-09-02 | |
| dc.date.copyright | 2015-09-02 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-08-03 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/53737 | - |
| dc.description.abstract | 肺癌高居全世界人類癌症死亡原因的榜首，每年約有百萬人死於肺癌，約佔癌症死亡率的27%。依照細胞型態的不同，肺癌又分成小細胞肺癌及非小細胞肺癌。被確診為肺癌的患者，其中85%屬於非小細胞肺癌。埃羅替尼（erlotinib）及吉非替尼（gefitinib）為美國食品和藥物管理局及日本所認可之用來針對非小細胞肺癌的標把藥物，但患者經過此種藥物的治療後一年會產生抗藥性。因此，尋找新型態藥物針對抗藥性的肺癌顯得更為重要。 2012年，由中央研究院基因體中心利用高通量藥物篩選系統從兩百萬種化合物資料庫中篩選出幾個先導化合物，其針對抗藥性及非抗藥性的非小細胞肺癌細胞株都有好的抑制效果，我們從中選一個嘌呤類的化合物為目標化合物，但其實際的抑制機制並不明確。在本篇論文中，我們合成了許多嘌呤類化合物的衍生物用來探討結構與活性之間的關係，並尋找適當的位置修飾上帶有生物素（biotin）的官能基，藉由嘌呤類化合物末端帶有生物素的官能基與抗生物素蛋白鏈菌素（streptavidin）之間的強作用力來尋找目標蛋白質。另外，我們所合成的一些嘌呤類化合物衍生物在生物實驗當中有好的抗癌效果。 | zh_TW |
| dc.description.abstract | Lung cancer remains a leading cause of cancer-related mortality in the world, estimated 1.3 million deaths per year to account for more than one-quarter (27%) of all cancer deaths. Lung cancer can be classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) according to the histological types, and almost 85% of lung cancer is diagnosed as NSCLC. Erlotinib and gefitinib, which belong to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, have been approved for the treatment of lung cancer by U.S. Food and Drug Administration (FDA) and in Japan. However, most patients may develop drug resistance and relapse one year after treatment. Thus, identifying new potent molecules for drug-resistant lung cancer treatment becomes an important therapeutic objective. Several NSCLC cell lines are used to select potent anticancer agents that may target either EGFR dependent or independent NSCLC. A purine-type compound was found as a hit by the high throughput screening against a library of two-million compounds in the Genomics Research Center (GRC) at Academia Sinica. In this thesis, we first report the synthesis of many purine-type compounds to study the structure–active relationship in an attempt to find better inhibitors. After finding the appropriate position for further modification of the purine-type compound, we also synthesized derivatives with a photoaffinity probe and a biotin label.. Through the collaboration with College of Medicine, National Taiwan University, the biotin-annexed compound was successfully used as a probe to catch the target proteins. Some of our synthesized purine-type compounds demonstrated good anticancer effects in the in vitro and in vivo assays. Further studies are ongoing to explore the purine-type compounds for a new therapy of drug-resistant NSCLC patients. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T02:28:37Z (GMT). No. of bitstreams: 1 ntu-104-R02223109-1.pdf: 10577167 bytes, checksum: 6f7b1c6f0fbaeb34a3cd13e54f26256e (MD5) Previous issue date: 2015 | en |
| dc.description.tableofcontents | Table of Contents Acknowledgement I Abstract in Chinese II Abstract in English III Table of Contents V Index of Schemes VII Index of Figures VIII Index of Tables IX Abbreviations XI Chapter 1. Introduction 1 1.1 Lung cancer 1 1.2 Cell cycle 6 1.3 Microtubule 7 1.4 Commercially available drugs for treating NSCLC 9 1.4.1 Chemotherapy 9 1.4.2 Targeting therapy 11 1.5 High throughput screening to search for novel drug hits 17 1.6 (Strept)avidin–biotin system 20 1.7 Photoaffinity labeling 21 Chapter 2. Results and Discussion 25 2.1 Previous research 25 2.2 Strategy for hit derivatization 28 2.3 Modification at N7- or O8-position 30 2.4 Finding the appropriate positions for further modifications 34 2.5 Replacement of O-atom with S-atom at 8-position 42 2.6 Derivatives modified from compound 7 and their anticancer activities in H1975 cells 47 2.7 Identification of katanin as a direct target 52 2.8 Conclusion 57 2.9 Prospect 60 Chapter 3. Experimental Section 65 3.1 General part 65 3.2 Synthesis and characterization of compounds 66 References 106 Appendix 115 Index of Schemes Scheme 1. Photolysis of arylazide 23 Scheme 2. Photolysis of diazirine 24 Scheme 3. Synthesis of compound 7 26 Scheme 4. Preparation of substituted benzaldehydes 35 Scheme 5. Addition reaction of DAMN (9) with various substituted phenyl isocyanates, followed by condensation with benzaldehydes, to give purine-type products 36 Scheme 6. (A) Synthesis of amine linkers 40a and 40d; (B) Synthesis of amide compounds 43a–43e. 39 Scheme 7. Synthesis of biotin annexed probes (45b and 45d) and control compound 46 41 Scheme 8. Synthesis of compounds 49 and 50 42 Scheme 9. Synthesis of S-alkylation compounds 51–57 46 Index of Figures Figure 1. Pie chart that indicates the risk of lung cancer 2 Figure 2. Different types of lung cancer and the percentage in all lung cancer patients 3 Figure 3. The percentage of treatments for NSCLC patients at different stages 5 Figure 4. Cell cycle: G1, Gap 1; S, Synthesis; G2, Gap 2; M, Mitosis. 6 Figure 5. A cartoon representation for the process of photoaffinity labeling 22 Figure 6. Mechanism of forming 8-oxopurine-6-carboxamides 27 Figure 7. Structural derivatization of purine-type compound 29 Figure 8. 1H NMR spectra of 7 in DMSO-d6 (A), in DMSO-d6/D2O = 9:1 (B), and after deprotonateion with K2CO3 in DMSO-d6 (C). 31 Figure 9. 1H NMR spectra of 7 (A) and 49 (B) in DMSO-d6 solution. 44 Figure 10. General structural feature of purine-type compounds possessing anticancer activity 59 Figure S1. The identification of direct target protein 156 Figure S2. Molecular docking mode of compound 7 with katanin 157 Figure S3. Another molecular docking mode of compound 7 with katanin 158 Figure S4. Molecular docking of compound 37h with katanin 159 Figure S5. Molecular docking of compound 55 with katanin 159 Index of Tables Table 1. Target drugs for lung cancer treatment 16 Table 2. Inhibitory activities (IC50) of gefitinib and compound 7 against different lung cancer cells and a normal cell 18 Table 3. Unsuccessful alkylation reactions of 7 33 Table 4. Synthesis of purine-type compounds 7 and 37a–37i from the coupling reactions of DAMN (9) with various phenyl isocyanates (R1C6H4N=C=O) and benzaldehydes (R2C6H4CHO). 37 Table 5. Inhibitory activity (IC50) of the purine-type compounds against the growth of H1975 cells 48 Table 6. Effect of R3 substituent in inhibition against H1975 cells 50 Table 7. Inhibitory activity (IC50) of the S-alkylation compounds against the growth of H1975 cells 51 Table 8. Calculated partition coefficient (clogP) of purine-type compound with different R1 and R2 substituents. 63 Table 9. Calculated partition coefficient (clogP) of R3 substituted purine-type compounds 63 Table 10. Calculated partition coefficient (clogP) of mercaptopurine compounds and S-alkylation compounds. 64 | |
| dc.language.iso | en | |
| dc.subject | 抗藥性 | zh_TW |
| dc.subject | 肺癌 | zh_TW |
| dc.subject | drug resistance | en |
| dc.subject | Lung cancer | en |
| dc.title | 針對抗藥性非小細胞肺癌之嘌呤類化合物的研究 | zh_TW |
| dc.title | Purine-type Compounds Targeting Gefitnib-resistant Non-Small Cell Lung Cancer | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 103-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 王宗興,潘思樺,陳榮傑 | |
| dc.subject.keyword | 肺癌,抗藥性, | zh_TW |
| dc.subject.keyword | Lung cancer,drug resistance, | en |
| dc.relation.page | 159 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2015-08-03 | |
| 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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