Biomedical subjects

S R Byrn

Publications and source records attributed to S R Byrn.

At least 37 records · Page 2Linked to original sources

PubMed1987

Effect of beta-alkyl substitution on D-1 dopamine agonist activity: absolute configuration of beta-methyldopamine.

beta-Methyldopamine and its enantiomers and racemic beta-phenyldopamine were synthesized and evaluated for dopamine D-1 agonist activity. In the dopamine-sensitive adenylate cyclase assay, beta-phenyldopamine had about one-sixth the activity of dopamine. Racemic beta-methyldopamine was less potent. The absolute configuration of beta-methyldopamine was determined to be R-(+) and S-(-). Evaluation of (R)-(+)- and (S)-(-)-beta-methyldopamine revealed no enantioselectivity for stimulation of adenylate cyclase.

Adenylyl Cyclases↗

PubMed1987

The solid-state decarboxylation of the diammonium salt of moxalactam.

This paper reports studies of the solid-state chemistry of the diammonium salt of moxalactam. The methods employed include X-ray crystallography, molecular mechanics calculations, thermogravimetric analysis, and high-pressure liquid chromatography. The crystal structure shows that the malonic acid amide functionality in crystals of the diammonium salt is not planar. If the common decarboxylation mechanism is operating, then considerable rotation would be required for this functionality to attain coplanarity. Simultaneous HPLC and thermogravimetric analysis studies indicate that the decarboxylation of the diammonium salt of moxalactam is preceded by desolvation. Molecular mechanics calculations indicate that the barrier to rotation of the malonic acid amide functionality is relatively small in the dehydrated crystals, perhaps explaining the facile decarboxylation of this antibiotic. Alternatively, the amorphous desolvated crystals may allow enough molecular freedom for the malonic acid amide functionality to attain coplanarity and decarboxylate.

Chromatography, High Pressure Liquid↗

PubMed1986

Conformation of glyburide in the solid state and in solution.

Nuclear magnetic resonance spectroscopy was combined with X-ray crystallography to determine the solution and solid-state conformations of glyburide (C23H28CIN3O5S). In solution, there is apparently free rotation about several of the single bonds. Crystals of glyburide belong to space group P2(1)/n with a = 9.414(3)A, b = 17.591(5)A, c = 14.410(4)A, beta = 93.42(3) degrees, V = 2382(1)A3, R = 0.0694, Z = 4. In the solid, the conformation about all of the bonds is frozen. The torsion angles about some of the important bonds are: C(7)-N(8)-C(9)-C(10), -86 degrees; N(8)-C(9)-C(10)-C(11), -179 degrees (extended); S(17)-N(18)-C(19)-N(20), 178 degrees (extended); and N(18)-C(19)-N(20)-C(21), -179 degrees (extended). Thus, except for the N(8)-C(9) bond, the conformation in the solid state is extended. The solution and solid-state NMR spectra are different as might be expected based on the differences in conformation discussed above.

Carbon Isotopes↗

PubMed1985

Analysis of solid-state Carbon-13 NMR spectra of polymorphs (benoxaprofen and nabilone) and pseudopolymorphs (cefazolin).

The solid-state 13C-NMR spectra of the polymorphs of benoxaprofen, nabilone, and cefazolin are reported using the cross-polarization/magic-angle spinning (CP/MAS) technique. In general, the spectra of the different crystal forms are different. In favorable cases the spectra of the drug in a pharmaceutical granulation can be discerned. These results provide a preliminary indication that solid-state NMR spectroscopy is a useful technique for the investigation of drug polymorphs and drugs in their dosage forms.

Anti-Inflammatory Agents↗

PubMed1984

Degradation of crystalline ergocalciferol [vitamin D2, (3 beta,5Z,22E)-9,10-secoergosta-5,7,10(19),22-tetra en-3-ol].

The products of the degradation of crystalline ergocalciferol were investigated. These studies showed that numerous acidic and neutral oxidation products were formed resulting in the complete destruction of the triene functionality. Separation of the neutral products by preparative TLC led to material identified as the Windaus ketone IIa, 2,3,3a,4,5,6,7,7a beta-octahydro-7a alpha-methyl-1R-(1 alpha,1R,4R,5-trimethyl-2E-hexenyl)-4H-inden-4-one.

Chromatography, Thin Layer↗

PubMed1982

The interaction of granaticin with nucleic acids and pyruvate decarboxylase.

The interaction of granaticin with two different yeast ribonucleic acids, dialyzed transfer RNA and calf thymus DNA was studied. Contrary to previous reports, no binding of granaticin to DNA or RNA was observed. The visible spectrum of granaticin on direct mixing or equilibrium dialysis of granaticin with RNA or DNA was unchanged. Furthermore, granaticin did not displace acridine orange from DNA in competitive binding studies using fluorescence polarization. However, granaticin was shown to inhibit pyruvate decarboxylase. From the Ki for granaticin (3.8 mM) it was concluded that granaticin is as efficient as other 1,4-naphthoquinones in inhibiting pyruvate decarboxylase.

Animals↗

PubMed1982

The desolvation and oxidation of crystals of dialuric acid monohydrate.

Examination of the influence of the solvent of crystallization on the solid-state oxidation of dialuric acid (I) monohydrate to alloxantin (II) is reported. This reaction was investigated at low and high humidities using photomicrography, X-ray crystallography, and IR and mass spectrometry. Crystals of dialuric acid desolvated somewhat anisotropically; this behavior was consistent with crystal packing. The desolvated crystals of dialuric acid monohydrate had approximately the same crystal structure as the monohydrate and were stable in air at room temperature at low humidities. At high humidity, these crystals rehydrated and rapidly oxidized to alloxantin. These studies showed for the first time that desolvation was not a necessary prerequisite to solid-state oxidation and that solid-state oxidation reactions could be accelerated by high humidity.

Barbiturates↗

PubMed1982

Solution conformation of the thermolysin inhibitors carbobenzoxy-L-phenylalanine and beta-phenylpropionyl-L-phenylalanine and comparison of the solution conformation to the enzyme-bound conformation.

The conformations of enzyme inhibitors in solution and bound to the enzyme thermolysin are investigated as a convenient model for understanding the relationship between the conformation of drugs in solution and at the receptor. The solution conformations of carbobenzoxy-L-phenylalanine (I) and beta-phenylpropionyl-L-phenylalanine (II) are determined using nuclear magnetic resonance spectroscopy. These studies show that I and II have essentially the same conformation about both the alpha-beta bond and the C alpha-N bond in Me2SO-d6, acetone-d6, methanol-d4, chloroform-d, and D2O. In addition, the conformations of I and II are similar to phenylalanine and other phenylalanine derivatives. Comparison of the lowest energy solution conformer to that bound by the enzyme thermolysin shows that the lowest energy conformer (in solution) of carbobenzoxy-L-phenylalanine is bound by thermolysin; on the other hand, it is the highest energy conformer (in solution) of beta-phenylpropionyl-L-phenylalanine which is bound to the enzyme. This, to our knowledge, is one of the first experimental conformations of the hypothesis that an enzyme does not always bind the lowest energy conformer of an inhibitor.

Kinetics↗

PubMed1981

Crystal structure and solid-state behavior of aspirin anhydride crystals.

The crystal structure and solid-state behavior of aspirin anhydride were determined using single-crystal X-ray techniques and microscopic examination of the reacting crystals. The crystal structure and solid-state conformation of aspirin anhydride were similar to those of related compounds. The crystal packing of aspirin anhydride allows the initial product of the solid-state reaction to be predicted; however, this prediction could not be tested because the thermal degradation products reported in the literature appear to be those obtained from reaction in a liquid state.

Anhydrides↗

PubMed1981

Comparisons of rotamer populations of nialamide, azaperone, and chloroquine in solid state and in solution.

IR and NMR spectroscopy were combined with previously published X-ray crystallographic data to determine the solution conformations of the -(CH2)n- fragments of nialamide, azaperone, and chloroquine. The solution conformation of these compounds then was compared to the solid-state conformation. In addition, the limits of the IR-X-ray method are discussed. This paper shows that a combination of IR, NMR, and X-ray crystallographic data can lead to a complete picture of the conformations available to drugs. In addition, the danger of using solid-state conformational data alone to make pharmacological suggestions is illustrated.

Azaperone↗

PubMed1981

Comparison of solution conformational preferences for the hallucinogens bufotenin and psilocin using 360-MHz proton NMR spectroscopy.

The 360-MHz 1H NMR spectra of bufotenin and psilocin were obtained, both as the free bases in CDCl3 and as protonated salts in D2O. Coupling constants for the side-chain methylenes were derived using the LAOCN3 program. These time-averaged coupling constants indicate that the trans and gauche rotamers of both compounds have about equal energy in D2O. There is a slight excess of the trans rotamer of bufotenin in CDCl3. For psilocin, in contrast, the gauche form is highly favored in CDCl3. The magnitude of this stabilization was estimated at about 1 kcal/mol using rotamer populations and free energy of transfer from published partitioning studies. It is suggested that this could result from a very weak hydrogen bond. On the other hand, the difference in partitioning between bufotenin and psilocin, which seems to be a major determinant of biological activity, is largely due to a difference in the basicity of the two compounds. The pKa values for the amino group of psilocin and bufotenin were determined to be 8.47 and 9.67, respectively.

Bufotenin↗

PubMed1978

Conformational analysis of pyridoxal Schiff's bases. Nuclear magnetic resonance studies of the conformations about the C4-C4', Calpha-Cbeta, and N-Calpha bonds of the pyridoxal Schiff's bases of amino acids.

The solution conformations of a series of pyridoxal-amino acid Schiff's bases were analyzed using 13C and 1H nuclear magnetic resonance techniques. The 13C--1H coupling constants were assigned based on model compounds and isotopic labeling. The predominant conformation of the the C4--C4' bond was found to be "cis" based on nuclear Overhauser effect (NOE) measurements and the "simultaneous" upfield shift of both H4' and H5' in the Schiff's bases of aromatic amino acids. Going from the monoanion (pD 8.2) to the dianion (pD 12.3), changes in these two effects suggested an increasing contribution of the "trans" conformer. The conformation of the N--Calpha bond was found to be approximately the same for all the Schiff's bases studied based on the long-range coupling constants 3J(C4'--Halpha) of these compounds, and the NOE studies indicate that there is a close spatial relationship between H4' and Halpha. The conformations of the Calpha--Cbeta bond of the Schiff's bases of aromatic amino acids were determined by stereospecific deuterium labeling at the beta position. A pi--pi interaction between the aromatic ring and the pi system of pyridoxal was observed which disappeared upon saturation of the aromatic ring.

Amino Acids↗

PubMed1978

Conformation-reactivity relationship for pyridoxal Schiff's bases. Rates of racemization and alpha-hydrogen exchange of the pyridoxal Schiff's bases of amino acids.

The role of stereoelectronic effects in controlling the reaction specificity of biological reactions involving pyridoxal phosphate-amino acid Schiff's bases was tested with nonenzymatic models. The rates of racemization and Halpha exchange of a series of pyridoxal-amino acid Schiff's bases were determined. The order of these rates does not parallel the predictions based solely on electronic or steric effect, but parallels the proportions of the reactive conformers (e.g., conformers with the Calpha--Halpha bond orthogonal to the pi system) estimated by CPK models. The special reactivity of the phenylalanine Schiff's base was consistent with a special conformation in which some type of pi--pi interaction increases the proportion of exchangeable conformers, thus further substantiating the role of conformation in governing the reactivity of the Calpha--Halpha bond. Furthermore, semiempirical calculations of the conformation about the Calpha00N bond were performed using the CAMSEA conformational analysis program. The results of conformational calculations are consistent with the results of conformational analysis by nuclear magnetic resonance. The order of reactivity of the the Calpha--Halpha bond of the SB dianion, pH 12.0, predicted by calculation based on stereoelectronic effects, though not quantatively parallel to the observed rate constants, is qualitatively in agreement with the experimental results.

Amino Acids↗

PubMed1978

Potential antitumor agents. Synthesis, reactivity, and cytoxicity of alpha-methylene carbonyl compounds.

The alpha-methylene lactones 9, 12, 21, and 24 were prepared by a mild, convenient alpha-methylenation process using the alpha-ethyloxalyl derivatives in nonoptimized yields ranging from 23 to 90%. The rates of reaction of these and several other lactones with cysteine at pH 7.4 and their KB toxicities were measured. These studies showed that neither the strained trans-fused alpha-methylene lactone 12 nor the hydroxy-alpha-methylene lactones 5 and 6 reacted with cysteine with rates comparable to elephantopin. Based on these limited studies, the rate of cysteine addition appears to be relatively insensitive to changes in strain energy and neighboring groups. In addition, the rate constant for reaction with cysteine did not correlate with cytotoxicity.

Antineoplastic Agents↗

PubMed1976