The biological action of substances related to thyroxine; the effect of n-alkyl 3:5-diiodo-4-hydroxybenzoates on oxygen consumption in mice.

Since the principle of competitive inhibition in chemotherapy was introduced by Woods (1940), several attempts have been made to prepare compounds with an inhibitory action against thyroxine. The first report of direct antagonism was that of Woolley (1946) who observed that a number of ethers of N-acetyldiiodotyrosine exhibited antithyroxine activity in amphibian metamorphosis. Harington (1948) suggested that it might be possible to distinguish between the effects of thyroxine on the pituitary and on the peripheral tissues. In an attempt to inhibit one or other of these effects he prepared the thio-ether analogue of thyroxine, but this proved to have thyroxine-like activity when tested in tadpoles. Also using tadpoles as test animals, Frieden & Winzler (1949) described the inhibitory action of a number of compounds, including the benzyl ethers of diiodotyrosine and 3:5diiodo-4-hydroxybenzoic acid, and produced evidence to support their view that this effect was due to true competitive inhibition. Cortell (1949) has demonstrated the antithyroxine properties of 2': 6'-diiodothyronine in rats by the goitre prevention method. The desirability of extending the methods of studying thyroxine inhibition in mammalia led us to develop a technique for determining the effects of such compounds on the rise of oxygen consumption produced by thyroxine in mice (Maclagan & Sheahan 1950). By this method one of the compounds described by Frieden & Winzler (1949), 4-benzyloxy3:5-diiodobenzoic acid, was found to be active, and subsequently, the dimethylacetal of 3:5-diiodoanisaldehyde (Wilkinson, 1949) also gave positive results (Maclagan, Sheahan & Wilkinson, 1949). A brief account of the effects of a series of n-alkyl 3:5-diiodo-4-hydroxybenzoates has already appeared (Wilkinson, Sheahan & Maclaganr, 1950), and it is the purpose ofthe present paper to discuss more fully the results obtained and also to extend the study to a number of related substances. Of the two methods available for the preparation of the n-alkyl 3:5-diiodo-4-hydroxybenzoates, that involving iodination of the n-alkyl p-hydroxybenzoates was preferred, since the alternative procedure of esterifying the diiodoacid invariably resulted in some decomposition, and in consequence the products proved difficult to purify. Most of the required alkyl hydroxybenzoates have been described by Cavill & Vincent (1947). Several diiodophenols were prepared by Paal (1895) by treatment of the phenols with two equivalents of iodine in aqueous ethanolic solution in the presence of the calculated quantity of iodic acid. As the acid conditions of this method were liable to cause hydrolysis of the esters, we replaced the iodic acid by an equivalent quantity of potassium iodate, and, by this means, the eight n-alkyl esters from methyl to n-octyl were obtained in good yields.