On the crystal structure of thyroxine

Abstract

The presence of four iodine atoms in the molecule of thyroxine directed our attention to the problem of determining its crystal structure.Samples of thyroxine and sodium thyroxine were kindly supplied by Dr A. B. Hems of Glaxo Laboratories, Greenford, Middlesex. As the DL-sodium salt was found to crystallize more readily and to form better crystals, it was decided to start work on that compound. Its chemical formula is I I I HO--~O-~,-CH2-CH(NH~)COONa • 5H~O.

Thyroxine revisited**This article includes supplementary material, available at www.interscience.wiley.com/jpages/0022‐3549/suppmat

“…No record in the literature could be found that Joel and Canepa1 have continued this study. The unit‐cell dimensions of the enantiomeric hydrated L ‐T 4 sodium salt measured over two decades later2 were in a reasonable agreement with those reported by Joel and Canepa,1 which could indicate that the racemic solution crystallized into a conglomerate. Unfortunately, the low quality of the sodium salts crystals and their reported gradual decay in radiation prevented the structural determinations.…”

“…Its capabilities of increasing the rates of chemical reactions in almost all cells of the body sparked much interest for understanding its docking in the active sites, and transport through the body and interactions between hormones and proteins or their functions in general. The molecular‐structure investigations of ±T 4 were initiated by Joel and Canepa1 in the 1950s by the X‐ray study of its racemic sodium salt: it resulted in the determination of the crystal unit‐cell dimensions, crystal density, and the [C 15 H 10 I 4 NO 4 ] − · Na + · 5H 2 O salt stoichiometry; based on the triclinic unit‐cell dimensions, and one Patterson projection giving a rough estimation of the iodine‐atoms positions, the crystal symmetry was assigned as $P\bar 1$ , implying its racemic composition. No record in the literature could be found that Joel and Canepa1 have continued this study.…”

“…The molecular‐structure investigations of ±T 4 were initiated by Joel and Canepa1 in the 1950s by the X‐ray study of its racemic sodium salt: it resulted in the determination of the crystal unit‐cell dimensions, crystal density, and the [C 15 H 10 I 4 NO 4 ] − · Na + · 5H 2 O salt stoichiometry; based on the triclinic unit‐cell dimensions, and one Patterson projection giving a rough estimation of the iodine‐atoms positions, the crystal symmetry was assigned as $P\bar 1$ , implying its racemic composition. No record in the literature could be found that Joel and Canepa1 have continued this study. The unit‐cell dimensions of the enantiomeric hydrated L ‐T 4 sodium salt measured over two decades later2 were in a reasonable agreement with those reported by Joel and Canepa,1 which could indicate that the racemic solution crystallized into a conglomerate.…”

Structure Elucidation and Characterization of Different Thyroxine Polymorphs

“…[5] Thedifference in bioavailability has been ascribed to variation in the drug formulation. [7] Earlier structural studies of different salts and co-crystals of T4 [8] indicated that this compound can exist in both cisoid and transoid conformations,w hich are determined by the relative orientation of the diiodophenolic ring with respect to the amino acid moiety.T he structure of T4 in as alt-free zwitterionic form is still unknown. Understanding the effect of conformational change on the reactivity of the C À Ibond is crucial since T4 is apro-hormone and the selective removal of iodine atoms from T4 by three selenoenzymes,t he iodothyronine deiodinases Dio1, Dio2, and Dio3 ( Figure S2 in the Supporting Information), is ak ey step in maintaining its biological activity through receptor binding and thyroid hormone homeostasis.…”

“…[7] Earlier structural studies of different salts and co-crystals of T4 [8] indicated that this compound can exist in both cisoid and transoid conformations,w hich are determined by the relative orientation of the diiodophenolic ring with respect to the amino acid moiety.T he structure of T4 in as alt-free zwitterionic form is still unknown. [8] Thep resent study indicates that the transoid conformer of T4 itself can exist in different polymorphic forms. [9] Interestingly,w hen the compound was crystallized from am ixture of acetonitrile and ammonia, relatively larger rhomboid-shaped monoclinic crystals (Form II) in the P2 1 space group were obtained.…”