發展八環 1,2-雙酮化學探針分子 選擇性標定含胍基化合物及其後續應用;Development of Dibenzocyclooctendione-based Probes for Specific Labeling of Arginine-Containing Molecules and Its Applications

Please use this identifier to cite or link to this item: http://ir.lib.ncu.edu.tw/handle/987654321/89177

Title:	發展八環 1,2-雙酮化學探針分子選擇性標定含胍基化合物及其後續應用;Development of Dibenzocyclooctendione-based Probes for Specific Labeling of Arginine-Containing Molecules and Its Applications
Authors:	施政廷;Shih, Cheng-Ting
Contributors:	化學學系
Keywords:	胍基;精胺酸;後轉譯修飾;1,2-雙酮;螢光團;抗體-藥物偶聯物;疊氮-炔烴環加成反應;guanidine group;arginine;post-translational modification;1,2-diketone;fluorophore;antibody-drug conjugates;azide-alkyne cycloaddition reaction
Date:	2022-08-12
Issue Date:	2022-10-04 11:00:22 (UTC+8)
Publisher:	國立中央大學
Abstract:	胍基常見於精胺酸(arginine)、胜肽、蛋白質以及生物分子中；蛋白質後轉譯修飾的精胺酸，其側鏈末端的胍基會轉變為脲(urea)官能基或進行甲基化，此代謝修飾已證實與疾病有所關連，例如:類風濕性關節炎、潰瘍性結腸炎、阿茲海默症、狼瘡或是癌症等，因此近年來有許多科學家致力於胍基的標定，然而大部分標定的反應需要強鹼或高溫等嚴苛的反應環境，所產生的不穩定加成產物也會因反應環境而緩慢水解，以上的因素也限制了它們在生物標定上的應用。在本論文中，我們合成ㄧ系列八環 1,2-雙酮的衍生物，在溫和的條件下，可與含胍基的化合物進行脫水重排反應，形成穩定的加成產物。另一方面，利用不同官能基取代的八環 1,2-雙酮衍生物，針對 1-甲基脲、1-甲基胍鹽酸鹽、1,2-二甲基胍氫溴酸鹽以及 1,1-二甲基胍鹽酸鹽探討其反應性；最後我們也將疊氮分子利用聚乙二醇鏈引入八環 1,2-雙酮衍生物，以便後續利用疊氮-炔烴環加成反應接上螢光團或是當作藥物-抗體偶聯物的修飾應用。;Guanidine is a small nitrogen-rich small compound and extremely common in biological systems. Guanidine functional groups are also frequently present in natural products, bioactive compounds and one of the most important pharmacophoric groups in medicinal chemistry. Furthermore, arginine citrullination and methylation are two universal post‑translational modifications on the side chain of arginine in natural peptides and proteins. Aberrant protein citrullination is relevant to several autoimmune and neurodegenerative diseases as well as some cancer formations. Aberrant histone arginine methylation is associated with carcinogenesis and metastasis have been well demonstrated. Until now, several studies have investigated the reactivity of arginine to various reagents for the chemical modifications of guanidine group of arginine in biomolecules. However, most of the labeling conditions are under strong base or high temperature harsh conditions that are not suitable for biological applications. In this thesis, we develop eight-membered 1,2-diketone derivatives (DBCDOs), which underwent an irreversible ring-contracted rearrangement with the guanidine group on arginine residue under mild reaction conditions. We also explore the reactivity of these 1,2-diketone probe derivatives and 1-methylurea, 1-methylguanidine hydrochloride, 1,2-dimethylguanidine hydrobromide and 1,1-dimethylguanidine hydrochloride. Finally, we also introduced the azide group into the eight-membered 1,2-diketone derivative by using the polyethylene glycol chain for subsequent applications, such as attachment of a fluorophore or as a drug-antibody conjugates.
Appears in Collections:	[Graduate Institute of Chemistry] Electronic Thesis & Dissertation

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