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Biomedical subjects

V Cody

Publications and source records attributed to V Cody.

At least 91 records · Page 5Linked to original sources
PubMed1982

Conformational effects of ether bridge substitution in thyroid hormone analogues.

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.

Ethers↗
PubMed1980

Role of iodine in thyroid hormones: molecular conformation of a halogen-free hormone analogue.

The molecular conformation of the halogen-free thyroid hormone analogue, N-acetyl-4'-methoxy-3,5,3'-trimethyl-L-thyronine ethyl ester, has beeen determined by X-ray diffraction techniques. The observed molecular conformation is similar to that found for the natural hormone 3,5,3'-triiodo-L-thyronine (T3). In this structure, the 3'-methyl group is distal, the overall conformation is cisoid, and the diphenyl ether conformation is twist--skewed. These structural similarities with T3 show that the conformation features required by the active hormone can still be maintained with methyl substitution. The observation that the halogen-free analogues have relatively high activity but extremely low protein binding affinity implies that the role of iodine in hormone transport and biological activity can be deifferentiated. These data suggest that the iodines enhance hormone--protein binding by virtue of their electronic, as well as steric, properties.

Chemical Phenomena↗
PubMed1979

Molecular conformation of thyroid hormones: structure and binding interactions of thyroxine.

In an accurately determined X-ray diffraction study of the thyroid hormone thyroxine (T4), the two independent conformations in the crystal lattice show significant differences in the outer phenyl ring geometry when compared with that of 3,5,3'-triiodothyronine (T3). The major differences between the T4 and T3 structures are a shortened C4'-O4' bond, contraction of the C3'-C4'-C5' angle and an increase in the C3' and C5' angles of T4. These changes can be correlated with the difference in acidity of the 4'-OH of T4 and T3 and help to explain binding affinity differences among thyroactive compounds. The hydrogen bond directionality observed in T4 and other thyroid structures offers an insight into the molecular details of the hormone-receptor site. The conformation of one T4 molecule is cisoid, that of the other transoid, the first such instance of different overall conformations to be found in the same crystal lattice. One T4 molecule has the side chain nearly coplanar with the inner ring, an unusual conformation among thyroid structures.

Models, Molecular↗
PubMed1978

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

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.

Models, Molecular↗
PubMed1977

Steroid structure and function:I. Conformational transmission in 17alpha-acetoxy progesterone.

The molecular conformation of 17alpha-acetoxy progesterone has been determined crystallographically and is compared with that of progesterone. The 17alpha-acetate substituent restricts the flexibility of the progesterone side chain, strains bond lengths in the C- and D-rings, and has long range effects on the A-ring conformation. The A-ring adopts a perfect sofa conformation similar to that observed in one conformational isomer of progesterone. Consequently this progesterone isomer is proposed to be that best suited to binding in the rabbit and human uterus.

Chemical Phenomena↗
PubMed1977

Molecular conformation of ammonium 8-anilino-1-naphthalenesulfonate hemihydrate. A fluorescent probe for thyroxine binding to thyroxine binding globulin.

The crystal and molecular structure of the ammonium hemihydrate salt of the fluorescent dye, 8-anilino-1-naphthalenesulfonic acid (ANS), has been determined. There are two conformationally distinct molecules in the triclinic P1 lattice. The anilino nitrogen of one molecule has slightly distorted planar geometry, and the overall conformation of the molecule is similar to that observed for the potassium salt of the fluorescent dye 2-p-toluidinyl-6-naphthalenesulfonic acid (TNS). The anilino nitrogen of the other molecule has slightly distorted tetrahedral geometry and the overall conformation of the molecule is similar to that observed for the thyroid hormones T3 and T4. The observation of two distinct conformational modifications of ANS in this crystal structure determination has shed light on the conformational flexibility of the ANS molecule itself and on the mode by which its acts as a competitive inhibitor in thyroid hormone transport proteins and as a signal for hydrophobic areas in macromolecular systems.

Anilino Naphthalenesulfonates↗
PubMed1977

Molecular structure of thyroxine analogues. Crystal structure of 3,5,3'-triiodothyroacetic and 3,5,3',5'-tetraoiodothyroacetic acid N-diethanolamine (1:1) complexes.

Crystallographic data demonstrated that conformations of thyroid hormones and their derivatives in which the phenyl rings are either skewed (phi,phi'; +/-90,0 degrees) or twist-skewed (phi,phi'; +/-108, +/-28 degrees) 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.

Chemical Phenomena↗
PubMed1976

NMR-studies of triiodothyropropionic acid in ethanol-HCl.

The barrier to rotation in the N-acetyl methyl ester of the thyroxine was found to be 8.6 kcal mol-1. Previous experiments determining the barrier to rotation in triiodothyropropionic acid in HCl-ethanol were shown to be in error.

Ethanol↗
PubMed1975

Distal conformation of thyroid hormones. Crystal and molecular structure of 3,5,3'-triiodo-L-thyronine methyl ester.

In the crystal structure of 3,5,3'-triiodo-L-thyronine methyl ester, the 3' -iodine is distal, i.e., away from the alanine bearing ring, and the overall conformation is cisoid, that is, the alanine moiety and the outer phenyl ring lie on the same side of the inner phenyl ring plane. This conformation, reported here, for the first time, is in contrast to the transoid conformation previously observed for thyroid hormone structures. The torsional angles between the diphenyl either linkages (theta and theta') are -108 and 33 degrees, respectively, while the C-O-C angle is 117 degrees. The value of chi1, which describes the amino acid backbone conformation, is 308 degrees. The structure crystallizes in the tetragonal space group P41 with a = 8.225 (5) and c = 28.42 (1) A. The final R index is 0.06.

Chemical Phenomena↗
PubMed1973

Distal conformation of the thyroid hormone 3,5,3'-triiodo-L-thyronine.

In the crystal structure of the thyroid hormone, 3,5,3'-triiodo-L-thyronine, the 3' iodine is observed in the distal position, away from the alaninebearing ring of the thyroid hormone. This result had been anticipated from stereochemical and biological activity studies. However, previous observations of structures in which the 3' iodine was proximal had cast some doubt on the stability of the 3' distal conformation. This observation suggests that the relative energies of the two conformers is similar and that perhaps the barrier to rotation is not as great as previously supposed since both the distal and proximal conformers have now been observed in the solid state.

Models, Structural↗