Molecular Structure of Thyroxine Analogs. Crystal Structure of 3,5,3′-Triiodothyroacetic and 3,5,3′,5′-Tetraiodothyroacetic Acid N-diethanolamine (1:1) Complexes

Crystallographic data demonstrate that conformations of thyroid hormones and their derivatives in which the phenyl rings are either skewed (ϕ,ϕ′±90,0°) or twist-skewed (ϕ,ϕ′±108, 28°) are energetically favored. Acetic acid metabolites are consistently observed in the skewed conformation whereas their parent hormones are observed in the twist-skewed conformation. These preferences are manifestations of long-range conformational transmission and together with plasma protein binding data may indicate a site-specific preference for the skewed vs. twist-skewed conformation. These findings result in part from the crystal structure determinations of the N-diethanolamine (1:1) complexes of the active thyroxine metabolites 3,5,3′-triiodothyroacetic acid (T₃AA) and 3,5,3′,5′-tetraiodothyroacetic acid (T₄AA) which are reported here. The conformation of the 3′-iodine in the hypocholestermic agent T₃AA is distal, the biologically preferred conformation, and the overall conformation of T₃AA is transoid, while that of T₄AA is cisoid.