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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 王宗興 | zh_TW |
| dc.contributor.advisor | Tsung-Shing Andrew Wang | en |
| dc.contributor.author | 蕭郁蓉 | zh_TW |
| dc.contributor.author | Yu-Rong Hsiao | en |
| dc.date.accessioned | 2025-11-27T16:11:05Z | - |
| dc.date.available | 2025-11-28 | - |
| dc.date.copyright | 2025-11-27 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-10-13 | - |
| dc.identifier.citation | 1. Pohl, C.; Dikic, I. Cellular quality control by the ubiquitin-proteasome system and autophagy. Science 2019, 366 (6467), 818–822.
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Chem. 2021, 30, 115932. | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/101078 | - |
| dc.description.abstract | 蛋白質降解靶向嵌合體(proteolysis-targeting chimeras, PROTACs)是一類新興的治療策略，能選擇性誘導蛋白降解，具有廣泛潛力，但其開發受限於分子量大、細胞通透性不足以及對連接子特性的高度依賴。為解決這些問題，我們建立了多樣化且便利的化學策略，能由醛類構件快速組裝不同的 PROTAC。第一種策略利用 Wittig 反應，在溫和條件下生成含丙烯醯胺的 PROTAC。第二種策略為接續的威悌反應及環張力促進疊氮-炔烴環加成反應(strain-promoted azide-alkyne cycloaddition, SPAAC)反應，先由帶有疊氮基的醛與膦鹽生成含丙烯醯胺的共價抑制劑(targeted covalent inhibitor, TCI)，再於細胞內與帶有 DBCO 基團的片段進行 SPAAC 反應，以降低分子量提升細胞穿膜性。第三種策略則結合硝酮生成(nitrone formation)與環張力促進炔烴-硝酮環加成反應(strain-promoted azide-nitrone cycloaddition , SPANC) 反應，透過醛與羥胺生成硝酮後，再與 DBCO 基團反應，構建多功能 PROTAC，並可修飾光敏保護基團以實現光控活性。綜合而言，這些方法提供了一個高效且靈活的平台，用於合成與功能篩選具治療潛力的PROTAC。 | zh_TW |
| dc.description.abstract | Proteolysis-targeting chimeras (PROTACs) are an emerging therapeutic strategy that selectively induces protein degradation, with broad potential but limited by large molecular weight, poor cell permeability, and strong dependence on linker properties. To address these issues, we developed convenient and versatile chemical strategies enabling rapid assembly of diverse PROTACs from aldehyde building blocks. The first strategy uses a Wittig reaction, generating acrylamide-containing PROTACs under mild conditions. The second employs a sequential Wittig–strain-promoted azide-alkyne cycloaddition (SPAAC) approach, where aldehydes bearing azides react with phosphonium salts to yield acrylamide-functionalized targeted covalent inhibitors (TCIs), which undergo intracellular strain-promoted azide-nitrone cycloaddition (SPANC) with DBCO fragments to improve permeability. The third combines nitrone formation with SPANC, where aldehydes and hydroxylamines form nitrones that react with DBCO groups to construct multifunctional PROTACs, allowing incorporation of photocaging groups for light-controlled activity. Together, these methods establish an efficient and flexible platform for the synthesis and functional screening of PROTACs with therapeutic potential. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2025-11-27T16:11:05Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2025-11-27T16:11:05Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | Table of Content
摘要 i Abstract ii 謝誌 iii Table of Content iv Table of Figure viii Table of Scheme xii Abbreviations xiii Chapter 1 Introduction 1 1.1. Proteolysis-Targeting Chimeras (PROTAC) 1 1.2. Multifunctional PROTACs 2 1.3. Rapid PROTAC Assembly via Click Reaction 4 1.4. The Application of Aldehyde-Containing Building Blocks 5 1.5. Convenient Multi-Functional PROTACs Assembly with Aldehyde Building Blocks 7 1.5.1. The Wittig Reaction Represents a Promising Strategy for PROTAC Assembly 9 1.5.2. Strain-Promoted Alkyne- Nitrone Cycloaddition (SPANC) Represent a Promising Strategy for Multi-Functional PROTAC 11 Chapter 2 Results and Discussions 13 2.1. WT-PROTACs (Wittig PROTACs) 13 2.1.1. Molecular Design of WT-PROTACs 13 2.1.2. Preparation of AldeX-TH 14 2.1.3. WT-PROTACs Assembling via Purified and Preassembled Method 16 2.1.4. Evaluation of WT-PROTACs in Ramos Cells 22 2.1.5. Synthesis of E-form Ibr-AAMPS-TH 26 2.1.6. Cell Viability Assay of WT-PROTACs 29 2.2. WT-SPA PROTACs (Wittig-SPAAC PROTACs) 30 2.2.1. Molecular Design of WT-SPA PROTAC 30 2.2.2. Evaluation of WT-TCIs in Ramos Cells 32 2.2.3. Evaluation of WT-SPA-PROTACs in Ramos cells 35 2.2.4. Cell Viability Assay of WT-SPA-PROTACs 44 2.3. SPN-PROTACs (SPANC-PROTACs) 45 2.3.1. Molecular Design of SPN-PROTACs 45 2.3.2. Preparation of DBCO-VHL and X-NHOH 46 2.3.3. SPN-PROTACs Assembly and Their Evaluation in MDA-MB-231 Cells 48 2.3.4. Cell Viability Assay of SPN-PROTACs 63 2.3.5. Molecular Docking of SPN-PROTACs via AutoDock Vina 63 Chapter 3 Conclusions and Perspectives 68 Chapter 4 Materials and Methods 71 4.1. General Synthetic Methods and Instrumentation 71 4.2. Synthesis and Characterization of Compounds 72 4.2.1. Preparation of AldeX-TH 72 4.2.2. Preparation of E-form Ibr-AAMPS-TH 82 4.2.3. Preparation of DBCO-VHL and X-NHOH 87 4.2.4. WT-PROTACs Assembly 93 4.2.5. SPN-PROTACs Assembly 93 4.2.6. Photolysis Assay 94 4.2.7. Molecular Docking 94 4.3. Biological Experiment 95 4.3.1. Cell Culture 95 4.3.2. Cell Treatment for Western Blot Analysis 95 4.3.4. Western Blot Analysis 97 4.3.5. Cell Viability Assay 97 References 100 Appendix 110 | - |
| dc.language.iso | en | - |
| dc.subject | 蛋白質降解靶向嵌合體 | - |
| dc.subject | 醛類 | - |
| dc.subject | 威悌反應 | - |
| dc.subject | 疊氮–炔烴環加成 | - |
| dc.subject | 炔烴–亞硝基環加成 | - |
| dc.subject | 多重成分組裝 | - |
| dc.subject | 光保護基 | - |
| dc.subject | PROTAC | - |
| dc.subject | aldehyde | - |
| dc.subject | Wittig reaction | - |
| dc.subject | azide–alkyne cycloaddition | - |
| dc.subject | alkyne–nitrone cycloaddition | - |
| dc.subject | multi-component assembly | - |
| dc.subject | photocage | - |
| dc.title | 以含醛建構單元實現便利且多元組裝的多功能蛋白質降解靶向嵌合體 | zh_TW |
| dc.title | Convenient and Versatile Assembly of Multi-Functional PROTACs Using Aldehyde Containing Building Blocks | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 114-1 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 朱忠瀚;謝俊結 | zh_TW |
| dc.contributor.oralexamcommittee | John Chu;Jiun-Jie Shie | en |
| dc.subject.keyword | 蛋白質降解靶向嵌合體,醛類威悌反應疊氮–炔烴環加成炔烴–亞硝基環加成多重成分組裝光保護基 | zh_TW |
| dc.subject.keyword | PROTAC,aldehydeWittig reactionazide–alkyne cycloadditionalkyne–nitrone cycloadditionmulti-component assemblyphotocage | en |
| dc.relation.page | 126 | - |
| dc.identifier.doi | 10.6342/NTU202504571 | - |
| dc.rights.note | 同意授權(全球公開) | - |
| dc.date.accepted | 2025-10-14 | - |
| dc.contributor.author-college | 理學院 | - |
| dc.contributor.author-dept | 化學系 | - |
| dc.date.embargo-lift | 2030-10-12 | - |
| 顯示於系所單位： | 化學系 | |
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