2023-01-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/651465生物正交反應與點擊反應在生醫研究中有廣泛應用，特別是連結反應可用於產生具有生物活性的多功能性複合物。然而，多數連結反應缺乏可控制性，且反應完所後留下不可忽視的連結結構，使後續的生醫應用有所限制。在本計畫中，我們目標在能拓展有機反應，如：威悌反應與羥醛縮合反應，使其轉換成新穎水相相容連結反應。這兩個反應可用來原位生成活性官能基丙烯醯胺官能基，而丙烯醯胺常出現在標靶共價抑制劑中，我們的反應將可用於設計丙烯醯胺類標靶共價抑制劑(TCI)的前驅藥物。其次，我們也會設計高度彈性策略，用來整合可控制侷限單元到連結反應中，包含了威悌反應、羥醛縮合反應及硝酮參與環加成。這需要建構可控制被侷限的羰基化合物、N-單取代羥胺及環狀硝酮，且可用來控制蛋白降解靶向嵌合體(PROTAC)的原位組裝。最後，我們會利用基於新穎水相相容連結反應所設計的新型代謝物探針，其可用來側寫活性羰基化合物，這也將使我們可以設計出新型標靶共價抑制劑前驅藥，可響應細胞內活性羰基化合物並原位再生活性共價基團。 Biorthogonal reactions, or click reactions, have broad applications in biological and medical researches, Specifically, conjugation reactions are frequently used to prepare bioactive multi-functional conjugates. However, most of conjugation reactions leave unignorable structural scars at ligation sites and lack general controllability, which might limit their expandability. In this proposal, we aim to expand common organic reactions, such as Wittig reactions and aldol condensations, into novel aqueous compatible conjugation reactions. These two reactions are able to “in situ” construct the reactive acrylamide moiety, commonly found in many targeted covalent inhibitors (TCIs), and therefore make TCI prodrugs possible. In addition, we will design a highly versatile strategy to integrate tunable controllable cages into many conjugation reactions, including Wittig reactions, aldol condensations and nitrone involved cycloadditions. Specifically, caged carbonyl compounds, N-monosubstituted hydroxylamines and cyclic nitrones will be constructed to control the “in situ” assembly of proteolysis targeting chimeras (PROTACs). Finally, we will demonstrate that metabolomic probes based on our novel aqueous compatible conjugation reactions are able to profile the reactive carbonyl compounds. Therefore, design of novel TCI prodrugs is possible, in which “in situ” maturation of their reactive warheads can respond cellular reactive carbonyl compounds.水相相容連結反應;標靶共價抑制劑;蛋白降解靶向嵌合體;代謝物探針;威悌反應;羥醛縮合反應;硝酮;aqueous compatible conjugation reactions; targeted covalent Inhibitors; proteolysis targeting chimeras; metabolomic probes; Wittig reaction; aldol condensation; nitrone