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Biomedical subjects

V Cody

Publications and source records attributed to V Cody.

At least 73 records · Page 4Linked to original sources
PubMed1987

Conformational analysis of lipophilic antifolates: crystal and molecular structures of three s-triazine dihydrofolate reductase inhibitors.

The results of crystal structure determinations on a series of protonated N1-phenyl-substituted 1,2-dihydro-2,2-dimethyl-4,6-diamino-s-triazine anti-cancer antifolates show that the s-triazine ring adopts a twist-sofa conformation with C2 nearly 0.5 A above the plane and the N1-phenyl ring is nearly perpendicular to the s-triazine ring, in agreement with minimum energy calculations and with antifolate binding in the active site of chicken liver dihydrofolate reductase. The 2,2-dimethyl groups are equatorial and axial. Comparison of these s-triazines with analogous pyrimidine antifolates reveals that the axial 2-methyl group occupies the same conformational space as the 6-methyl group in active anti-cancer agents.

Crystallization↗
PubMed1986

Inhibition of rat liver iodothyronine deiodinase. Interaction of aurones with the iodothyronine ligand-binding site.

We report that aurone derivatives of plant extracts produce potent, dose-dependent, and ultimately complete inhibition of three different metabolic monodeiodination pathways catalyzed by rat liver microsomal type I iodothyronine deiodinase. These data show that (3'),4',4,6-(tetra)trihydroxyaurones are the most potent naturally occurring plant-derived inhibitors of this deiodinase enzyme (IC50 V 0.5 microM). Lineweaver-Burk analysis using both L-thyroxine (T4) and 3',5',3-triiodothyronine as substrates suggests a cofactor competitive mechanism of inhibition for 4',4,6-trihydroxyaurone which also can displace 125I-L-T4 from binding to thyroxine-binding prealbumin with a potency comparable to its inhibition of T4-5'-deiodinase. Among type I deiodinase inhibitors, cofactor competition has been observed only for propylthiourea. Computer graphic modeling studies were also carried out to explore aurone conformations and to compare them with those of the thyroid hormones. This analysis shows that the aurones can adopt either a planar or an antiskewed conformation, such as observed for 3',5',3-triiodothyronine, the most potent natural deiodinase substrate inhibitor. The thyroxine-binding prealbumin complex was used to model the deiodinase ligand binding site because of the similarity observed between inhibitor binding affinity and enzyme inhibition characteristics. These studies show that the aurones which adopt an antiskewed conformation can interact favorably in the prealbumin binding site. This model of the deiodinase active site can be used to design other deiodinase inhibitors.

Animals↗
PubMed1986

Rat liver iodothyronine monodeiodinase. Evaluation of the iodothyronine ligand-binding site.

Ligand binding characteristics of rat liver microsomal type I iodothyronine deiodinase were evaluated by measuring dose-response inhibition and apparent Michaelis-Menten or inhibitor constants of iodothyronine analogues to compete as substrates or inhibitors for the natural substrate L-thyroxine. These data show strong correlations with the binding requirements of hormone analogues to serum thyroxine-binding prealbumin since iodothyronine analogues with a negatively charged side chain, a negative charge or hydrogen bonding function in the 4'-position, tetraiodo ring substitution, and a skewed hormone conformation are structural features shared in common which markedly affect enzyme activity and protein binding affinity. 3,3',5'-Triiodo-L-thyronine is the most potent natural substrate (IC50 = 0.3 microM) and tetraiodothyroacetic acid is the most potent inhibitor (IC50 = 0.2 microM). Both thyroxine (T4)-5'- and T4-5-deiodination pathways are inhibited by these potent analogues, providing further evidence for a single enzyme catalyzing the rat liver microsomal deiodination reactions. These data also show that L-hormone analogues are preferentially deiodinated via the T4-5'-deiodination pathway, whereas D-analogues produce products via the T4-5-deiodination pathway. The thyroxine-binding prealbumin complex was used to model the interaction of thyroid hormones with the deiodinase active site. Computer graphic modeling of the prealbumin complex showed that only those analogues which are potent deiodinase inhibitors or substrates can be accommodated in the hormone binding site. This model suggests the design of functionally specific ligands which can modulate peripheral thyroid hormone metabolism and act as antithyroidal drugs.

Animals↗
PubMed1986

Crystal structure of phlorizin and the iodothyronine deiodinase inhibitory activity of phloretin analogues.

Phloretin, a 7,8-dihydrochalcone of plant origin, and the high molecular weight (less than 15,000) polyphloretinphosphate (PPP) polymers are potent inhibitors of iodothyronine monodeiodinase activity from rat liver microsomal preparations, whereas phlorizin, the 2'-O-glucoside of phloretin, is inactive. The polymers, differing in degree of phosphorylation-dependent polymerization, exhibited a concentration-dependent, and ultimately complete, inhibition of deiodinase activity with an IC50 between 0.2 and 0.5 micrograms PPP/ml. Phloretin inhibition, on the other hand, was cofactor (DTE) competitive, with a Ki = 0.75 microM. 2',4',6',3,4- Pentahydroxychalcone, which has a substitution pattern in the A-ring identical to that of phloretin, was the only active inhibitor (IC50 = 8 microM) among several derivatives tested. The phloretin biodegradation products, phloretic acid and phloroglucinol, and its biosynthetic precursors, monomeric cinnamic acid and cinnamic acid derivatives, were inactive in concentrations up to 100 microM. The X-ray crystal structure analysis of phlorizin dihydrate showed that the molecule is planar and fully extended, similar to the conformation observed in chalcone structures that are characterized by an alpha, beta-unsaturated bond between phenol rings. Comparison of the planar phlorizin crystal structure with a skewed or antiskewed thyroid hormone conformation revealed that the beta-D-glucose moiety does not share any of the thyroid hormone's conformational space, and that the best structural homology is found with the antiskewed conformation of 3',5',3-triiodothyronine, the natural deiodinase substrate that also inhibits further deiodination.

Animals↗
PubMed1985

Milrinone and thyroid hormone stimulate myocardial membrane Ca2+-ATPase activity and share structural homologies.

We have recently shown that thyroid hormone in physiological concentrations stimulates sarcolemma-enriched rabbit-myocardial-membrane Ca2+-ATPase in vitro. In this study, milrinone [2-methyl-5-cyano-(3,4'-bipyridin)-6(1H)-one], a cardiac inotropic agent, was thyromimetic in the same system. At clinically achievable concentrations (50-500 nM), milrinone significantly stimulated membrane Ca2+-ATPase in vitro. This action was antagonized by W-7 [N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide], an agent that also blocks thyroid hormone action on the Ca2+-ATPase, at concentrations as low as 5 microM. Progressive additions of milrinone to membranes incubated with a fixed concentration of thyroxine (0.10 nM) or triiodothyronine resulted in a progressive obliteration of the thyroid hormone effect on Ca2+-ATPase. Amrinone [5-amino-(3,4'-bipyridin)-6(1H)-one], the parent bipyridine of milrinone, had no effect on myocardial Ca2+-ATPase activity. X-ray crystallographic analysis of milrinone and amrinone revealed structural homologies between the phenolic ring of thyroxine and the substituted ring of milrinone, whereas amrinone did not share these homologies. The mechanism(s) of the inotropic actions of thyroxine and of milrinone is not clearly understood, but these observations implicate Ca2+-ATPase, a calcium pump-associated enzyme, as one mediator of the effects on the heart of these two compounds.

Aminopyridines↗
PubMed1985

Conformational analysis of environmental agents: use of X-ray crystallographic data to determine molecular reactivity.

This paper explores the use of crystallographic techniques as an aid in understanding the molecular reactivities of a number of agents that are of concern to pharmacologists and toxicologists. The selected examples demonstrate the role of structural data in the determination of absolute configuration, configurational flexibility and active-site topology for a reactive species. For example, the role of absolute stereochemistry in understanding synthetic pyrethroid structure-activity relationships is shown from analysis of their crystal structures; conformational flexibility among DDT analogues, and the importance of conformational and electronic properties in phenylalkanoic acid herbicides are shown from systematic analysis of their crystal structures; and interpretation of active-site stereochemistry is made by study of computer modeling of enzyme inhibitors in the active sites of related protein crystal structures. Thus, the observed patterns in conformational flexibility and their resultant effects on substrate pharmacological profile can be interpreted in understanding the molecular level events that influence biological reactivity.

Crystallography↗
PubMed1985

Conformational analysis of erythrosine B (FD&C Red No. 3) and its comparison with thyroid hormone structures.

Erythrosine B, also known as FD&C Red No. 3, is a tetraiodofluorescein dye that is widely used as a biological stain and color additive in food and drugs. Recent data show that erythrosine B and Rose Bengal, its polychlorophenyl derivative, are potent inhibitors of both 5'-T4 and 5-T4 monoiododeiodinase activity. However, fluorescein, the nonhalogenated parent compound, has no effect on deiodinase activity. The X-ray crystal structure of erythrosine B was determined to elucidate the structural basis for its competition with T4 for its hormone protein binding sites. These structural results show that the dye crystallizes as a free acid-ethanol solvate. The relative orientation of the benzoic acid and xanthine moieties is nearly perpendicular, similar to that observed in the structure of fluorescein. As frequently noted in thyroid hormone structures, there are short I...I and I...O contact distances in this structure. Because of the symmetric iodophenolic substitution pattern of the xanthine ring, there will always be one iodophenolic ring that is not homologous with the thyroid hormone structure. Therefore, this analysis suggests that the best conformational homology is achieved when the dye phenolic ring is matched with that of a skewed thyroid hormone structure.

Binding Sites↗
PubMed1984

Molecular structure and biochemical activity of 3,5,3'-triiodothyronamine.

The thyroid hormone decarboxylation product, 3,5,3'-triiodothyronamine (T3AM), has been shown to inhibit the cAMP production stimulated by isoproterenol in turkey erythrocytes. This adrenergic receptor binding inhibition was not shown by the thyroid hormones nor by tyramine, but was observed for 3,5-diiodotyramine, 3,5-diiodothyronamine, and thyronamine. T3AM also inhibits prolactin secretion in cultured pituitary cells as well as domperidon binding in rat corpora striata membranes. T3AM has no thyromimetic activity at the nuclear level. The molecular structure of T3AM, determined as a borosalicylate salt by X-ray diffraction techniques, is the first report of a decarboxylated thyroid hormone analogue.

Animals↗
PubMed1983

Stimulation by thyroid hormone analogues of red blood cell Ca2+-ATPase activity in vitro. Correlations between hormone structure and biological activity in a human cell system.

Human red blood cell membrane Ca2+-ATPase activity is stimulated in vitro by physiological concentrations (10(-10) M) of L-thyroxine (L-T4) and 3,5,3'-triiodo-L-thyronine (L-T3). This human cell system has been utilized to examine a series of iodothyronine and iodotyrosine analogues for structure-activity relationships. Analogue purity was verified by high pressure liquid chromatography. Analogues were studied at a concentration of 10(-10) M and the stimulatory effect of each analogue was compared with that of L-T4 in this system. Essential to Ca2+-ATPase stimulation were occupation of the 3 and 5 phenyl positions by iodide, bromide, or methyl groups, the L-configuration of the alanine side chain, side chain length equal to that of alanine, and a perpendicular (skewed) conformation of the two rings. The 4'-hydroxyl group is not essential to Ca2+-ATPase stimulation in this model system. T3 was 76% as active as T4 in stimulating Ca2+-ATPase activity. The stimulatory effect of 3,5-dimethyl-3'-isopropyl-L-thyronine and 3,5,3',5'-tetrabromo-L-thyronine approximated that of L-T4. Selected tyrosine analogues also stimulated the enzyme. The bioactivities of hormone analogues in this human model of extra-nuclear thyroid hormone action differ in several ways from results obtained previously in other animal model systems in vitro and in vivo.

Calcium-Transporting ATPases↗
PubMed1983

CNDO/2 molecular orbital calculations on the antifolate DAMP and some related species: structural geometries, ring distortions, change distributions and conformational characteristics.

Geometry-optimized CNDO/2 molecular orbital calculations were carried out on 2, 4-diamino-5-(1-adamantyl 1)-6-methyl pyrimidine (DAMP), a potent inhibitor of mammalian dihydrofolate reductase which is now in clinical trials, and on its inactive 5-(1-naphthyl) analogue (DNMP-1). Crystallographic data show that DAMP (as the ethylsulfonate salt) has a severely distorted, N1 protonated, pyrimidine ring and has steric crowding of the 6-methyl and adamantyl hydrogens whereas DNMP-2 (as a methanol complex) has a planar, nonprotonated pyrimidine ring that is nearly perpendicular to the naphthalene ring. The CNDO/2 results largely reproduce the crystal structure geometry and show that the ring distortions in DAMP are initiated by steric conflicts between the adamantyl group and the 4- and 6-substituents on the ring. In DNMP-1, the non-interfering naphthyl ring induces little strain within the pyrimidine ring and the effect of protonation is negligible. Rotation about the bond joining the two ring groups is restricted in DAMP by a broad barrier of ca. 8.0 kcal mol-1, and no conformation was successful in relieving steric conflicts and hence reducing the ring distortions. In DNMP-1, rotation is less hindered overall with a broad region of accessible conformational space and a maximum barrier of ca. 7.2 kcal mol-1 for the coplanar conformation. The electronic charge distributions of DAMP and DNMP-1 are almost identical and protonation is preferred at N1 rather than at N3 by ca. 3.7 kcal mol-1 for both DAMP and DNMP-1. The calculations establish that the present methodology can be useful as a predictive tool with regard to the structure and conformational characteristics of these and related species.

Adamantane↗
PubMed1983

Crystallographic studies of the antineoplastic antifolate 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine (DDMP) ethanesulfonate salt.

The lipid-soluble diaminopyrimidine, 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine (DDMP) binds tightly to dihydrofolate reductase and has antineoplastic activity in man and several animal systems. The x-ray crystal structure of this antifolate, as the ethanesulfonate salt, was studied to investigate the conformational aspects of its binding specificity. The molecular conformation shows the dichlorophenyl ring nearly perpendicular (phi = 110 degrees) to the pyrimidine ring which is coplanar with its 2,4,6-substituents. the protonated N1 atom of the pyrimidine ring forms a hydrogen bond to an ethanesulfonate oxygen, as do both N2 and one of N4 hydrogens. The other N4 hydrogen participates in an inversion related base-pair type of hydrogen bond with N3 of a neighboring molecule, similar to patterns observed in other diaminopyrimidine antifolates.

Antineoplastic Agents↗
PubMed1982

Molecular structures of 2,4-diaminopyrimidine antifolates with antineoplastic activity.

2,4-Diamino-5-(1-adamantyl)-6-methylpyrimidine (DAMP) and its ethanesulfonate salt (DAMP-ES) are potent inhibitors of mammalian dihydrofolate reductase and also inhibit the growth of cultured cells as effectively as the drug methotrexate (MTX). DAMP is currently in phase I clinical studies. An analogue of DAMP having 5-(1-naphthyl) in place of the adamantyl group (DNMP) possesses little cytotoxic as well as enzyme inhibitory activity. The crystal and molecular structures of DAMPM-ES and DNMP were determined in order to elucidate the conformational aspects of drug specificity. The molecular conformation of DAMP-ES shows that the C8--C7 bond of the adamantyl ring is nearly coplanar with the pyrimidine ring (C8--C7--C5--C6 = 7.5 degrees) instead of staggered as expected from steric considerations. As a result, the pyrimidine ring and its 4,6-substituents are severely distorted from coplanarity. In DNMP, the 1-naphthalene ring is perpendicular to the pyrimidine ring (C8--C7--C5--C6 = -87.0 degrees) which is itself planar. N1 is protonated in DAMP-ES but not in DNMP. When the two structures are compared, the 5-substituents occupy different regions of space, with the outer ring of the naphthalene group outside of the volume occupied by the adamantyl ring. Therefore, the reduced effectiveness of DNMP may be caused by the inability of the naphthalene to fit the binding site in dihydrofolate reductase. This is the situation when DNMP is placed in the methotrexate binding site of Lactobacillus casei crystal structure.

Antineoplastic Agents↗