Radovanovic, Milica (1999) Synthesis of novel thyroid hormone analogues. Research Master thesis, Victoria University of Technology.

Abstract

A series of twenty two 2-phenoxybenzoic acids were prepared in various yields using two different methods. It was found that the method involving a modified Ullmann coupling of a phenol with 2-chlorobenzoic acid gave the best yields. Reaction between diphenyliodo-2-carboxylate and a phenoxide gave lower yields and xanthone as byproduct. Using the modified Ullmann reaction 3-phenoxybenzoic acid and two thiophenoxybenzoic acids were also prepared in good yield. Transthyretin (TTR) was isolated from human plasma by column chromatography and the prepared phenoxybenzoic acids were tested for binding to the isolated protein. The most potent compounds were found to be 3-phenoxybenzoic acid (26), 2-(2,4- dimethylphenoxy)benzoic acid (10), 2-(2,3-dimethylphenoxy)benzoic acid (9) and 2- (3-iodophenoxy)benzoic acid (25). All of the compounds tested were up to two orders of magnitude less active than the corresponding nitrogen bridged anthranilic acids, indicating that replacing the nitrogen atom with either an oxygen or sulfur lowers activity. Interestingly, 3-phenoxybenzoic acid binds more strongly to TTR than 2-phenoxybenzoic acid and is almost as active as 2-phenoxyanthranilic acid, indicating that the preparation of analogues with the carboxylic acid in alternative positions on the ring may lead to even more potent anti-thyroid drugs.

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