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Molecular conformation of a halogen-free thyroxine analog: 4-Methoxy-3,5,3-trimethyl-L-thyronine N-acetyl ethyl ester

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Science  22 Sep 1978:
Vol. 201, Issue 4361, pp. 1131-1133
DOI: 10.1126/science.684433

Abstract

The molecular conformation of the halogen-free thyroxine analog 4-methoxy-3,5,3'-trimethyl-L-thyronine -n-acetyl ethyl ester has been determined by x-ray diffraction techniques. The unsubstituted parent compound, trimethylthyronine, has significant biological activity in rat thymocyte tests when compared with the thyroid hormone 3,5,3'-triiodo-L-thyronine (T3). Although no activity data are available for the analog studied, it is presumed to be inactive because of the 4-methoxy blocking group. The observed conformation of this structure is similar to that found for the natural hormone T(3). The 3'-methyl group is distal, the overall conformation is cisoid, and the diphenyl ether conformation is twist-skewed. The results of this diffraction study show that methyl substituents are capable of maintaining the thyronine conformation required for hormonal activity; they suggest that iodine enhances hormone-protein binding because of the electronic effects it produces either by alteration of molecular charge distributions or by direct charge-transfer interactions with the serum or nuclear binding proteins.