合成2-芐氧基苯甲酸類衍生物做為神經節糖?GM1接受體抑制劑; Synthesis of 2-(benzyloxy)benzoic acid derivatives as the inhibitor of ganglioside GM1 receptor .

CMUR > College of Pharmacy > Graduate Institute of Pharmaceutical Chemistry > Theses & dissertations > Item 310903500/24725

Please use this identifier to cite or link to this item: http://ir.cmu.edu.tw/ir/handle/310903500/24725

Title:	合成2-芐氧基苯甲酸類衍生物做為神經節糖?GM1接受體抑制劑;Synthesis of 2-(benzyloxy)benzoic acid derivatives as the inhibitor of ganglioside GM1 receptor .
Authors:	王志文;Wang Chin-Wen
Contributors:	中國醫藥大學藥物化學研究所
Keywords:	下痢;2-芐氧基苯甲酸;接受體;抑制劑;神經節糖?;毒素;霍亂;腹瀉;水瀉;環狀腺核?單磷酸;忌熱型腸毒素;非抗生素;忌熱型腸;吸附法;刺激型;化合物;相似性;氯離子;王志文;忌熱型腸;吸附法;刺激型;化合物;相似性;diarrhea;ADP;Ribosylation;ganglioside;GM1;receptor;benzyloxy;benzoic acid;isophthalic acid;methoxy;naphthoic acid;cAMP;LT;CT;enterotoxin;cholera toxin;ELISA;heat-labile;AB5;toxin;wang;design
Date:	2004
Issue Date:	2010-01-20 16:55:22 (UTC+8)
Abstract:	在生化結構研究上發現由產毒性大腸桿菌(ETEC)所分泌的忌熱型腸毒素(LT)與霍亂弧菌所分泌的霍亂毒素(CT)結構有非常大的相似性，對於毒素的作用機轉之闡明已經可以達到分子甚至原子如此細微的等級。毒素五元的次單元B會辨認人類小腸上皮細胞GM1接受器，並引發細胞的內吞作用(endocytosis)而將毒素帶入細胞內，毒素的A1蛋白片段可使α刺激型Ｇ蛋白(Gsα)與鳥嘌呤核?三磷酸(GTP)持續維持在結合狀態，此複合物會活化腺核甘環狀?(adenyl cyclase) 造成環狀腺核?單磷酸(cAMP)不斷的被製造，使cAMP濃度上升，造成細胞內離子及水份大量流出至腸腔，引起水瀉症狀產生。對於抑制毒素次單元B接受體的化學結構設計上，延續先前的研究成果，以2-[(4-methoxybenzyl)oxy]benzoic acid (31)為先導化合物，合成了一系列2 (or 3 or 4)-substituted benzyloxy benzoic acids、4 (or 5 or 6)-methoxy-2-substituted benzyloxy benzoic acids、4-substituted benzyloxy isophthalic acids、1 or 3-substituted benzyloxy -2-naphthoic acids、 2-substituted benzyloxy-1-naphthoic acids以及針對benzoic acid羧基延長的化合物。在生物活性篩選上我們藉由GM1-酵素結合免疫吸附法(GM1-ELISA)測定活性，並以老鼠做毒素下痢分析的動物實驗，其結果顯示4 or 6-methoxy-2- substituted benzyloxy benzoic acids及3-substituted benzyloxy benzoic acids 具有明顯的抗下痢活性，值得更進一步研究。; Structural biology studies on heat-labile enterotoxin (LT) from enterotoxigenic Escherichia coli. and the closely related cholera toxin (CT), shed light on the action mechanism of toxin at molecular and atomic levels. The B pentamer protein of the toxins recognized the receptor ganglioside GM1 presented on the gastrointestinal tract of human host and triggers endocytosis . The enzymatic A1 fragment of the toxin enters the cytosol it modifies the alpha subunit of stimulatory G protein (Gsα) and locks the G protein in its GTP-bound form, which continually stimulates adenylate cyclase to produce cAMP. The resulting elevate levels of cAMP cause dramatic efflux of ions and water from the host, leading to watery diarrhea. Structure-based design has led to various classes of compounds targeting toxin B subunit bonding site in our Laboratory. Following the previous results, 2-[(4-methoxybenzyl)oxy]benzoic acid (31) was used as a lead compound, a series of 2 (or 3 or 4)-substituted benzyloxy benzoic acids, 4 (or 5 or 6)-methoxy-2-substituted benzyloxy benzoic acids, 4-substituted benzyloxy isophthalic acids, 1 or 3-substituted benzyloxy-2-naphthoic acids, 2-Substituted benzyloxy-1-naphthoic acids and carboxyl group extend of benzoic acids were synthesized. The biological activities of these syntheted compound were examined by GM1 Enzyme-linked Immunosorbent Assay (GM1-ELISA) and Patent Mouse Gut Assay, the result showed 4 or 6-methoxy-2-substituted benzyloxy benzoic acids and 3-substituted benzyloxy benzoic acids have significant anti-diarrhea activities and worthy for further investigation.
Appears in Collections:	[Graduate Institute of Pharmaceutical Chemistry] Theses & dissertations

Files in This Item:

File	Description	Size	Format
index.html		0Kb	HTML	171	View/Open

Loading...