In previous papers from this laboratory (1-4) the synthesis of various compounds of general structure I, related to thyroxine, was reported. In structure I, R = -CH2CH2COOH, -CH2CH(NH2) COOH, -NH2, etc; X= iodine; X'= iodine, methyl, etc.; and R'= methyl or hydrogen.
X' XRoO -S-0-R X' X I In an accompanying paper (5), an empirical correlation between structure and biological activity for 47 analogs of structure I was proposed. The above correlation, while entirely empirical in nature, suggested significant deductions about the essential pharmacogen which is required for thyroxinelike activity. It also led to the conclusions that structural parameters, such as the electron-releasing abilities of X, X' and OR', the hydrogen bonding abilities of X and X' and the pK values for the compounds (dependent on the nature of the ionizing side chain, R), are the probable factors which determine the comparative biological activity of these substances. Of major importance to our thinking in arriving at the correlative conclusions was the very striking fact (5) that the 3',5'-dimethyl analogs of L-and D,L-thyroxine (structure I, X= iodine, X'= methyl, R'= H) were distinctly more active (5), in certain assays of thyroxine-like activity, than the corresponding stereoisomers of thyroxine. The suggestion that substitution of electron-releasing groups, such as methyl, in place of electron-attracting groups such as iodine, bromine, nitro, and so forth, can enhance thyroxine-like activity is a novel one and is in direct opposition to earlier considerations pertaining to such effects (5, 6).The postulate of the Bruice-Kharasch-9. This analysis was carried out in the laboratory of Dr.In previous papers from this laboratory (1-4) the synthesis of various compounds of general structure I, related to thyroxine, was reported. In structure I, R = -CH2CH2COOH, -CH2CH(NH2) COOH, -NH2, etc; X= iodine; X'= iodine, methyl, etc.; and R'= methyl or hydrogen.X' X
