Synthesis of 2-(benzyloxy)benzoic acid derivatives as the inhibitor of ganglioside GM1 receptor .

• Main Authors: Wang Chin-Wen, 王志文
• Other Authors: Huang Li-Jiau
• Format: Others
• Language: zh-TW
• Published: 2005
• Online Access: http://ndltd.ncl.edu.tw/handle/38257738085262709567

碩士 === 中國醫藥大學 === 藥物化學研究所 === 93 === 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.