Conformational effects of ether bridge substitution in thyroid hormone analogues.

Abstract

It has been suggested that the oxygen bridge linking the two iodophenyl rings of the thyroid hormones at an angle of 120 degrees promotes electron transfer between the rings or establishes the proper stereochemical relationship between the rings. To determine the effects of oxygen bridge substitution on conformation, an analysis of the X-ray crystal structures of a number of oxygen bridge analogues (NH, CO, CHOH, S) was undertaken and the results compared with the thyroid hormone structures. The 3,5-iodine substituents cause the two phenyl rings to adopt a skewed or twist-skewed conformation. The phenyl rings of all bridge substituted analogues can adopt these hormone conformations. There is a correlation between the bridging bond length and the bridging angle that tends to keep the overall diphenyl ring conformation constant. The results of sulfur bridge substitution have further structural implications with regard to the design of novel hormone analogues.