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PubMed1982

Solubilization and reconstitution of an amiloride-inhibited sodium transporter from rabbit kidney medulla.

An octyl glucoside extract has been formed from rabbit kidney medulla microsomes from which reconstituted proteoliposomes can be formed by lipid addition and dialysis to remove detergent. These proteoliposomes are capable of amiloride-inhibited 22Na+ transport. The amiloride-inhibited Na+ transport process is complete within 10 min and directly proportional to the vesicle protein concentration. Sodium accumulation by the proteoliposomes has been proven to represent transport by the demonstration that all Na+ taken up by the vesicles can be removed by the ionophore nigericin. The process has been shown to be specific for amiloride by the demonstration that the effect of amiloride on Na+ transport could not be reproduced by the similar compound sulfaguanidine nor by pyrazine, 2-pyrazinecarboxamide, 2-pyrazinecarboxylate, or 3-amino-2-pyrazinecarboxylate. The relationship between Na+ uptake into proteoliposomes and Na+ concentration was similar to the relationship between Na+ uptake and concentration observed with medulla microsomes. The concentration of amiloride required for half-maximal inhibition of Na+ uptake into either proteoliposomes or medulla microsomes was also the same. The evidence seems clear that the protein responsible for amiloride-inhibited Na+ transport into rabbit kidney medulla microsomes has been extracted from the membranes and incorporated into purified lipid vesicles.

Amiloride↗

PubMed2001

Stereospecific interaction of a novel spirosuccinimide type aldose reductase inhibitor, AS-3201, with aldose reductase.

Aldose reductase (AR) is an NADPH-dependent enzyme implicated in diabetic complications. AS-3201 [(R)-(-)-2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3'-pyrrolidine-1,2',3,5'-tetrone] is a structurally novel and potent ARI with an inhibitor constant (K(i) = 10(-)(10) M) 2000-fold lower than that of its optical antipode (S-isomer). To elucidate the inhibition modes and the stereochemical differences in their inhibitory potencies, we examined the interaction of these R- and S-isomers with AR under physiological conditions. Enzyme kinetic analysis, which was performed by using physiological substrates at 37 degrees C, showed that both isomers selectively act on the E-NADP(+) complex in both the forward and reverse reactions of AR. However, fluorometric titration analysis demonstrated that the affinities of the isomers for the E-NADP(+) complex are about the same as those for the E-NADPH complex and the apoenzyme. These results suggested that the selective binding to the E-NADP(+) complex arises from the predominance of this enzyme form during steady-state turnover rather than from binding specificity. Both the competition with a known active site-directed ARI and the protective effect on AR inactivation by N-bromosuccinimide showed that the isomers bind to the active site of the enzyme, but the thermodynamic parameters for the binding to AR indicated that additional hydrogen bonds and/or van der Waals interactions contribute to the energetic stabilization in the E-R-isomer complex. Molecular modeling, together with the deductions from spectroscopic studies, suggested that the succinimide ring and the 4-bromo-2-fluorobenzyl group of the R-isomer are optimally located for formation of a hydrogen-bonding network with AR, and that the latter benzyl group is also effective for the differentiation between AR and aldehyde reductase (a closely related enzyme).

Aldehyde Reductase↗

PubMedDate not supplied

Bayesian neural networks for aroma classification.

Bayesian Neural Networks (BNNs) are investigated to test their potential to distinguish between different aroma impressions. Special attention is thereby drawn on mixed aroma impressions, resulting from the flavor description of a single compound with more than one aroma quality. The structures of 133 pyrazine-derived aroma compounds as well as their aroma descriptions are selected for comparison. The information fed into the neural networks is based on molecular descriptors calculated from the geometrically optimized chemical structures. While in the case of the Probabilistic Neural Network (PNN) the networks' output consists of a categorical variable, the output for the General Regression Neural Network (GRNN) is defined in a numerical way. The best models attain comparable performance with a correct prediction of 90.8% of the cases for PNN and 89.9% for GRNN, respectively. Comparison of the BNN results to those obtained by Multiple Linear Regression (MLR) points out that the nonlinear methods work significantly better on the studied problem and that BNNs can be applied to multiple-category problems in structure-flavor relationships with good accuracy.

Bayes Theorem↗

PubMed2003

Incorporation of unprotected heterocyclic side chains into peptoid oligomers via solid-phase submonomer synthesis.

Peptoids (N-substituted glycines) are an important class of biomimetic oligomers that have made a significant impact in the areas of combinatorial drug discovery, gene therapy, drug delivery, and biopolymer folding in recent years. Sequence-specific peptoid oligomers are easily assembled from primary amines by the solid-phase submonomer method. However, most amines that contain heterocyclic nitrogens in the side chain do not incorporate efficiently. We present here a straightforward revision of the submonomer method that allows efficient incorporation of unprotected imidazoles, pyridines, pyrazines, indoles, and quinolines into oligomers as long as 15 monomers in length. This improved method uses chloroacetic acid instead of bromoacetic acid in the acylation step of the monomer addition cycle, and allows for the incorporation of new side chains that should enable the synthesis of peptoids with entirely new properties.

Acylation↗

PubMed2004

Thermodynamics of binding of 2-methoxy-3-isopropylpyrazine and 2-methoxy-3-isobutylpyrazine to the major urinary protein.

In the present study we examine the thermodynamics of binding of two related pyrazine-derived ligands to the major urinary protein, MUP-I, using a combination of isothermal titration calorimetry (ITC), X-ray crystallography, and NMR backbone (15)N and methyl side-chain (2)H relaxation measurements. Global thermodynamics data derived from ITC indicate that binding is driven by favorable enthalpic contributions, rather than the classical entropy-driven hydrophobic effect. Unfavorable entropic contributions from the protein backbone and side-chain residues in the vicinity of the binding pocket are partially offset by favorable entropic contributions at adjacent positions, suggesting a "conformational relay" mechanism whereby increased rigidity of residues on ligand binding are accompanied by increased conformational freedom of side chains in adjacent positions. The principal driving force governing ligand affinity and specificity can be attributed to solvent-driven enthalpic effects from desolvation of the protein binding pocket.

Amino Acid Sequence↗

PubMed2005

Synthesis of cyclic endiamino peptides.

Several building blocks for endiamino peptides, as well as several cyclic endiamino peptides themselves, and pyrazin-6-one, which embodies the endiamino group, were prepared. The variety of synthesized compounds shows the potential of this synthesis in the preparation of many different groups of compounds.

Alanine↗

PubMed2001

Optimizing headspace temperature and time sampling for identification of volatile compounds in ground roasted Arabica coffee.

Equilibration time and temperature were the factors studied to choose the best conditions for analyzing volatiles in roasted ground Arabica coffee by a static headspace sampling extraction method. Three temperatures of equilibration were studied: 60, 80, and 90 degrees C. A larger quantity of volatile compounds was extracted at 90 degrees C than at 80 or 60 degrees C, although the same qualitative profile was found for each. The extraction of the volatile compounds was studied at seven different equilibration times: 30, 45, 60, 80, 100, 120, and 150 min. The best time of equilibration for headspace analysis of roasted ground Arabica coffee should be selected depending on the chemical class or compound studied. One hundred and twenty-two volatile compounds were identified, including 26 furans, 20 ketones, 20 pyrazines, 9 alcohols, 9 aldehydes, 8 esters, 6 pyrroles, 6 thiophenes, 4 sulfur compounds, 3 benzenic compounds, 2 phenolic compounds, 2 pyridines, 2 thiazoles, 1 oxazole, 1 lactone, 1 alkane, 1 alkene, and 1 acid.

Alcohols↗

PubMed2002

Use of gas chromatography-olfactometry to identify key odorant compounds in dark chocolate. Comparison of samples before and after conching.

After vacuum distillation and liquid-liquid extraction, the volatile fractions of dark chocolates were analyzed by gas chromatography-olfactometry and gas chromatography-mass spectrometry. Aroma extract dilution analysis revealed the presence of 33 potent odorants in the neutral/basic fraction. Three of these had a strong chocolate flavor: 2-methylpropanal, 2-methylbutanal, and 3-methylbutanal. Many others were characterized by cocoa/praline-flavored/nutty/coffee notes: 2,3-dimethylpyrazine, trimethylpyrazine, tetramethylpyrazine, 3(or 2),5-dimethyl-2(or 3)-ethylpyrazine, 3,5(or 6)-diethyl-2-methylpyrazine, and furfurylpyrrole. Comparisons carried out before and after conching indicate that although no new key odorant is synthesized during the heating process, levels of 2-phenyl-5-methyl-2-hexenal, Furaneol, and branched pyrazines are significantly increased while most Strecker aldehydes are lost by evaporation.

Aldehydes↗

PubMed2002

Antioxidative activity of heterocyclic compounds found in coffee volatiles produced by Maillard reaction.

Typical heterocyclic compounds substituted with various functional groups found in Maillard reaction products were examined for antioxidant activity. Pyrroles exhibited the greatest antioxidant activity among all heterocyclic compounds tested. All pyrroles inhibited hexanal oxidation by almost 100% at a concentration of 50 microg/mL over 40 days. Addition of formyl and acetyl groups to a pyrrole ring enhanced antioxidative activity remarkably. Pyrrole-2-carboxaldehyde, 2-acetylpyrrole, 1-methyl-2-pyrrolecarboxaldehyde, and 2-acetyl-1-methylpyrrole inhibited hexanal oxidation by >80% at 10 microg/mL. Unsubstituted furan exhibited the greatest antioxidant activity among furans tested. Addition of all functional groups used in this study to furan decreased antioxidative activity. The antioxidant activity of thiophene increased with the addition of methyl and ethyl groups, but the addition of formyl or acetyl groups to thiophene decreased antioxidant activity. Thiazoles and pyrazines were ineffective antioxidants at all concentrations tested. Reaction of all heterocyclic compounds with hydrogen peroxide resulted in the formation of various oxidized products.

Aldehydes↗

PubMed2003

Chemoenzymatic synthesis of aroma active 5,6-dihydro- and tetrahydropyrazines from aliphatic acyloins produced by baker's yeast.

Twenty-five acyloins were generated by biotransformation of aliphatic aldehydes and 2-ketocarboxylic acids using whole cells of baker's yeast as catalyst. Six of these acyloins were synthesized and tentatively characterized for the first time. Subsequent chemical reaction with 1,2-propanediamine under mild conditions resulted in the formation of thirteen 5,6-dihydropyrazines and six tetrahydropyrazines. Their odor qualities were evaluated, and their odor thresholds were estimated. Among these pyrazine derivatives, 2-ethyl-3,5-dimethyl-5,6-dihydropyrazine (roasted, nutty, 0.002 ng/L air), 2,3-diethyl-5-methyl-5,6-dihydropyrazine (roasted, 0.004 ng/L air), and 2-ethyl-3,5-dimethyltetrahydropyrazine (bread crustlike, 1.9 ng/L air) were the most intensive-smelling aroma active compounds.

Aldehydes↗

PubMed1999

Effect of high hydrostatic pressure on the volatile components of a glucose-lysine model system.

An aqueous glucose-lysine model system (initial pH 10.1) was incubated at 60 degrees C and atmospheric pressure (system A) or 600 MPa (system B) to the same absorbance value at 420 nm. Volatile reaction products were isolated by solvent extraction and analyzed by gas chromatography/mass spectrometry. Thirty-two compounds were identified; most contained nitrogen, and pyrazines predominated. Yields of all compounds were suppressed at 600 MPa. Further incubation, at either atmospheric pressure (system C) or 600 MPa (system D), of system A, resulted in lower yields of many compounds at 600 MPa, compared to prolonged incubation at atmospheric pressure. Many of the compounds reported may be formed by, or subsequently react via, aldol condensation. The observed differences among the systems in the profiles and yields of volatile compounds suggest that aldol condensations increase in rate in the systems under pressure.

Furans↗

PubMed2001

Antimycobacterial activity of substituted isosteres of pyridine- and pyrazinecarboxylic acids. 2.

Pyridines and pyrazines substituted with 1,2,4-oxadiazole-5-ones, 1,2,4-oxadiazole-5-thiones, and 1,3,4-oxathiazoline-2-ones were synthesized and tested against Mycobacterium tuberculosis. The two former ring systems were documented in the literature to act as carboxylic acid isosteres. The latter series was synthesized as possible synthetic intermediates to 1,2,4-thiadiazole-3-ones and was included in this study due to their interesting activity. Pivaloyloxymethyl derivatives of the isosteres were also prepared in order to increase their lipophilicity and therefore improve their cellular permeability. The derivatized isosteres were expected to be biotransformed by esterases to the active species after penetration of the mycobacterial cell wall. Biological properties of the compounds were compared with the unmodified polar isosteres of pyrazinoic and nicotinic acids. The majority of the compounds exhibited activities ranging from 0.5 to 16 times the potency of pyrazinamide.

Antitubercular Agents↗

PubMed1985

Synthesis and antimetastatic properties of stereoisomeric tricyclic bis(dioxopiperazines) in the Lewis lung carcinoma model.

Synthesis of trans- and cis-tetrahydrodipyrazino[1,2-a:1',2'-d] pyrazine-1,3,7,9(2H,4H,8H,10H)-tetrone analogues 10 and 11 belonging to the bis(dioxopiperazine) class of antitumor agents and their bis(morpholinomethyl) derivatives 12 and 13 are described with use of 2,5-dimethylpyrazine as the starting material. Synthetic studies utilizing 3,6-disubstituted 2,5-dioxopiperazine precursors are included. Evaluation of 10-13 in the Lewis Lung carcinoma model indicated the bis(morpholinomethyl) analogue cis-13 to be antimetastatic, whereas the trans isomer 12 was toxic at a similar dose effecting a decrease in the life span of treated mice. The parent bis(dioxopiperazines) 10 and 11 were ineffective as antitumor or antimetastatic drugs.

Animals↗

PubMed2003

New isomeric azine-bridged dinuclear platinum(II) complexes circumvent cross-resistance to cisplatin.

Four new isomeric azine-bridged complexes ([(cis-Pt(NH(3))(2)Cl)(2)(mu-pzn)]Cl(2) (1a) (pzn = pyrazine) and its corresponding nitrate salt (1b), [(cis-Pt(NH(3))(2)Cl)(2)(mu-pmn)]Cl(2) (2) (pmn = pyrimidine), and [(cis-Pt(NH(3))(2)Cl)(2)(mu-pdn)](NO(3))(2) (3) (pdn = pyridazine) have been newly synthesized as potential anticancer compounds. These complexes have been characterized by (1)H and (195)Pt NMR spectroscopy, and also the X-ray crystal structure of 1b has been determined. The reactions of 1a, 2, and 3 with guanosine-5'-monophosphate (GMP) have been monitored and kinetically investigated in D(2)O solutions at 310 K using (1)H NMR spectroscopy. Both 1a and 2 react with 2 equiv of GMP to form 1:2 complexes. The reactions involve a stepwise direct substitution of chloride ligands by GMP, with similar reaction rates for both complexes. On the other hand, the reaction of 3 with GMP results in the cleavage of one of the Pt-N(pyridazine) bonds to form an N7,O6-platinated polymer. The reaction products have been separated and have been characterized by (1)H and (195)Pt NMR spectroscopy. A cytotoxicity assay of the azine-bridged complexes (1a, 1b, 2, and 3) has been performed on human tumor cell lines and two L1210 murine leukemia cell lines (one sensitive to and one resistant to cisplatin). In general, the complexes show lower cytotoxicity than cisplatin for the human tumor cell lines except for the IGROV cell line. Their cytotoxicity for the mouse cell lines is comparable to or higher than that of cisplatin. Furthermore, these complexes appeared to largely or partly overcome the cross-resistance to cisplatin. Implications of these findings are discussed in the context of a structure-activity relationship for this class of compounds.

Animals↗

PubMed2002

II. Synthesis and biological evaluation of some bioisosteres and congeners of the antitumor agent, 2-(4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy)propionic acid (XK469).

XK469 (1) is among the most highly and broadly active antitumor agents to have been evaluated in our laboratories. Subsequent developmental studies led to the entry of (R)-(+) 1 (NSC 698215) into phase 1 clinical trials (NIH UO1-CA62487). The antitumor mechanism of action of 1 remains to be elucidated, which has prompted a sustained effort to elaborate a pharmacophoric pattern of 1. The present study focused on a strategy of synthesis and biological evaluation of topologically based, bioisosteric replacements of the quinoxaline moiety in the lead compound (1) by quinazoline (4a-d), 1,2,4-benzotriazine (12a-18b), and quinoline (21a-g) ring systems. The synthetic approach to each of the bioisosteres of 1 utilized the methodology developed in previous work (see Hazeldine, S. T.; Polin, L.; Kushner, J.; Paluch, J.; White, K.; Edelstein, M.; Palomino, E.; Corbett, T. H.; Horwitz, J. P. Design, Synthesis, and Biological Evaluation of Analogues of the Antitumor Agent 2-(4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy)propionic acid (XK469). J. Med. Chem. 2001, 44, 1758-1776.), which is extended to the procurement of the benzoxazole (23a,b), benzthiazole (23c,d), pyridine (25a,b), and pyrazine (27) congeners of 1. Only quinoline analogues, bearing a 7-halo (21a,b,d,e) or a 7-methoxy substituent (21g), showed antitumor activities (Br > Cl > CH(3)O > F approximately I), at levels comparable to or greater than the range of activities manifested by 1 and corresponding analogues. At high individual dosages, the (S)-(-) enantiomers of 1 and 21b,d all produce a reversible slowing of nerve-conduction velocity in the mice, the onset of which is characterized by a distinctive dysfunction of the hind legs, causing uncoordinated movements. The condition resolves within 5-10 min. However, at higher dosages, which approach a lethal level, the behavior extended to the front legs, lasting from 20 min to 1 h. By contrast, the (R)-(+) forms of these same agents did not induce the phenomenon of slowing of nerve-conduction velocity.

Animals↗

PubMed2003

Aloisines, a new family of CDK/GSK-3 inhibitors. SAR study, crystal structure in complex with CDK2, enzyme selectivity, and cellular effects.

Cyclin-dependent kinases (CDKs) regulate the cell cycle, apoptosis, neuronal functions, transcription, and exocytosis. The observation of CDK deregulations in various pathological situations suggests that CDK inhibitors may have a therapeutic value. In this article, we report on the identification of 6-phenyl[5H]pyrrolo[2,3-b]pyrazines (aloisines) as a novel potent CDK inhibitory scaffold. A selectivity study performed on 26 kinases shows that aloisine A is highly selective for CDK1/cyclin B, CDK2/cyclin A-E, CDK5/p25, and GSK-3 alpha/beta; the two latter enzymes have been implicated in Alzheimer's disease. Kinetic studies, as well as the resolution of a CDK2-aloisine cocrystal structure, demonstrate that aloisines act by competitive inhibition of ATP binding to the catalytic subunit of the kinase. As observed with all inhibitors reported so far, aloisine interacts with the ATP-binding pocket through two hydrogen bonds with backbone nitrogen and oxygen atoms of Leu 83. Aloisine inhibits cell proliferation by arresting cells in both G1 and G2.

Adenosine Triphosphate↗

PubMed2002

Synthesis and pharmacological characterization of novel analogues of the nicotinic acetylcholine receptor agonist (+/-)-UB-165.

(+/-)-UB-165 (1) is a potent neuronal nicotinic acetylcholine receptor (nAChR) ligand, which displays functional selectivity between nAChR subtypes. Using UB-165 as a lead structure, two classes of racemic ligands were synthesized and assessed in binding assays for three major nAChR subtypes (alpha4beta2, alpha3beta4, and alpha7). The first class of compounds comprises the three pyridine isomers 4-6, corresponding to the 3-, 2-, and 4-substituted pyridine isomers, respectively. Deschloro UB-165 (4) displayed a 2-3-fold decrease in affinity at alpha4beta2 and alpha3beta4 nAChR subtypes, as compared with (+/-)-UB-165, while at the alpha7 subtype a 31-fold increase in affinity was observed. At each of the nAChR subtypes, high affinity binding was dependent on the presence of a 3-substituted pyridine, and the other isomers, 5 and 6, resulted in marked decreases in binding affinities. The second class of compounds is based on replacing the pyridyl unit of 1 with a diazine moiety, giving pyridazine (7), pyrimidine (8), and pyrazine (9), which retain the "3-pyridyl" substructure. Modest reductions in binding affinity were observed for all of the diazine ligands at all nAChR subtypes, with the exception of 7, which retained potency comparable to that of 4 in binding to alpha7 nAChR. In functional assays at the alpha3beta4 nAChR, all analogues 4-9 were less potent, as compared with 1, and the rank order of functional potencies correlated with that of binding potencies. Computational studies indicate that the 3-substituted pyridine 4 and 2-substituted pyridine 5, as well as the diazine analogues 7-9, all conform to a distance-based pharmacophore model recently proposed for the alpha4beta2 receptor. However, the nicotinic potencies of these ligands vary considerably and because 5 lacks appreciable nicotinic activity, it is clear that further refinements of this model are necessary in order to describe adequately the structural and electronic demands associated with this nAChR subtype. This rational series of compounds based on UB-165 presents a systematic approach to defining subtype specific pharmacophores.

Animals↗

PubMed2005

Synthesis and structure-activity relationships of a new model of arylpiperazines. 8. Computational simulation of ligand-receptor interaction of 5-HT(1A)R agonists with selectivity over alpha1-adrenoceptors.

We have designed and synthesized a new series of arylpiperazines V exhibiting high 5-HT(1A)R affinity and selectivity over alpha(1)-adrenoceptors. The new selective 5-HT(1A)R ligands contain a hydantoin (m = 0) or diketopiperazine (m = 1) moiety and an arylpiperazine moiety separated by one methylene unit (n = 1). The aryl substituent of the piperazine moiety (Ar) consists of different benzofused rings mimicking the favorable voluminous substituents at ortho and meta positions predicted by 3D-QSAR analysis in the previously reported series I. In particular, (S)-2-[[4-(naphth-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-a]pyrazine [(S)-9, CSP-2503] (5-HT(1A), K(i) = 4.1 nM; alpha(1), K(i) > 1000 nM) has been pharmacologically characterized as a 5-HT(1A)R agonist at somatodendritic and postsynaptic sites, endowed with anxiolytic properties. Ligand (S)-9 is predicted, in computer simulations, to bind Asp(3.32) in TMH 3, Thr(5.39) and Ser(5.42) in TMH 5, and Trp(6.48) in TMH 6. We propose that agonists modify, by means of an explicit hydrogen bond, the conformation of Trp(6.48) from pointing toward TMH 7, in the inactive gauche+ conformation, to pointing toward the ligand binding site, in the active trans conformation.

Adenylyl Cyclases↗