5,6-Dihydroxyindole-2-carboxylic acid: a first principles density functional study

We report first principles density functional calculations for 5,6-dihydroxyindole-2-carboxylic acid (DHICA) and several oxidised forms. DHICA and 5,6-dihydroxyindole (DHI) are believed to be the basic building blocks of the eumelanins. Our results show that carboxylation has a significant effect on the physical properties of the molecules. In particular, the relative stabilities and the highest occupied molecular orbital-lowest unoccupied molecular orbital gaps (calculated with the DeltaSCF method) of the various redox forms are strongly affected. We predict that, in contrast to DHI, the density of unpaired electrons, and hence the ESR signal, in DHICA is negligibly small. (C) 2004 Elsevier B.V. All rights reserved.

N-3,5 '-cycloxanthosine, the first natural occurrence of a cyclonucleoside

An Eryus sp. of marine sponge from the Great Australian Bight has yielded the first reported natural occurrence of a cyclonucleoside, N-3,5'-cycloxanthosine. The structure of N-3,5'-cycloxanthosine was confirmed by detailed spectroscopic analysis and total synthesis.

Determination of the anomeric configurations of 2,3,4,6-tetra-O-acetyl-D-mannopyranosyl azide

The structures of 2,3,4,6-tetra-O-acetyl-alpha-D-mannopyranosyl azide and 2,3,4,6-tetra-O-acetyl-beta-D-mannopyranosyl azide were determined using X-ray crystallographic and one-dimensional NOESY techniques.

'Tetol': a stereo-rigid four-strand motif for alkali and alkaline earth metal ion coordination

The tetraalcohol 2,3,5,6-endo,endo,endo,endo-tetrakis(hydroxymethyl]bicyclo[2.2.1]heptane (tetol, 1) has been prepared and crystallises readily as the lithium(I) complex [Li(1)(2)]Cl, forming an oligomeric multi-chain structure in which pairs of alcohols from two crystallographically independent tetol molecules bind lithium ions tetrahedrally. However, formation of monomeric structures in solution is inferred from electrospray mass spectroscopy, which has also shown evidence of exchange of lithium ion in the complexed species by added alkaline earth ions. (C) 2000 Elsevier Science S.A. All rights reserved.

Effect of honey types and concentration on starch gelatinization

The complex and variable composition of honey, depending on source, season and processing, means different honey samples could cause variation in the characteristics of the finished product. The objective of this study was to determine how the minor components present in honey affect starch gelatinization. A Rapid Visco Analyser was used to measure changes in viscosity when unmodified maize starch was gelatinized in a honey or model sugar solution. When honey was compared to equivalent blends of sugars, there was an increase in starch viscosity with increasing levels of addition. However, at the same level, honey gave a lower viscosity than the blends of sugars. Honeys from different sources (differing in pH and amylase activity) show a varied effect on starch gelatinization, with starch viscosity increasing with addition level for six of the honeys, but decreasing with increasing addition level for two honey samples. Varying the pH also produced variation in starch gelatinization patterns between honey types. Between pH 3.0 and 4.0, starch viscosity was similar for all four honey types studied, while above this pH there were differences between all honey types. As expected, starch viscosity decreased as the solution pH neared the optimum for honey amylase activity (pH 5.3-5.6), though it did not increase as the pH moved away from the honey amylase activity optimum. Differences between honey samples, and between honey and a model sugar mixture, in their effect on starch gelatinization was attributed to honey amylase activity and the composition and concentration of minor organic compounds present. Crown Copyright (C) 2003 Published by Elsevier Ltd. on behalf of Swiss Society of Food Science and Technology

Thue's theorem and the diophantine equation x2 - Dy2 = ±N

A constructive version of a theorem of Thue is used to provide representations of certain integers as x(2) - Dy-2, where D = 2, 3, 5, 6, 7.

Carbene and nitrene rearrangements: A theoretical study of cyclic allenes and carbenes, carbodiimides, and azirines

B3LYP/6-31G(d) calculations of structures, energies, and infrared spectra of several rearrangement products of (hetero)aromatic nitrenes and carbenes are reported. 3-Isoquinolylnitrene 36 ring closes to the azirine 37 prior to ring expansion to the potentially stable but unobserved seven-membered-ring carbodiimide 38 and diazacycloheptatrienylidene C-s-39S. A new, stable cycloheptatrienylidene, C-s-19S, is located on the naphthylcarbene energy surface. 4-Quinolylnitrene undergoes reaction via the azirine 50 in solution, but ring expansion to the stable seven-membered-ring ketenimine 47 under Ar matrix photolysis conditions. There is excellent agreement between calculated infrared spectra of 1,5-diazacyclohepta-1,2,4,6-tetraene 54 (obtained by photolysis of 4-pyridyl azide), 1-azacyclohepta-1,2,4,6-tetraene 5, 1-azacyclohepta-1,3,5,6-tetraene 55, and 1-azacyclohepta-1,3,4,6-tetraene 56 and the available experimental data.

Development of a fully quantitative approach to the interpretation of stress echocardiography using radial and longitudinal myocardial velocities

Background: Tissue Doppler may be used to quantify regional left ventricular function but is limited by segmental variation of longitudinal velocity from base to apex and free to septal walls. We sought to overcome this by developing a composite of longitudinal and radial velocities. Methods and Results. We examined 82 unselected patients undergoing a standard dobutamine echocardiogram. Longitudinal velocity was obtained in the basal and mid segments of each wall using tissue Doppler in the apical views. Radial velocities were derived in the same segments using an automated border detection system and centerline method with regional chords grouped according to segment location and temporally averaged. In 25 patients at low probability of coronary disease, the pattern of regional variation in longitudinal velocity (higher in the septum) was the opposite of radial velocity (higher in the free wall) and the combination was homogenous. In 57 patients undergoing angiography, velocity in abnormal segments was less than normal segments using longitudinal (6.0 +/- 3.6 vs 9.0 +/- 2.2 cm/s, P = .01) and radial velocity (6.0 +/- 4.0 vs 8.0 +/- 3.9 cm/s, P = .02). However, the composite velocity permitted better separation of abnormal and normal segments (13.3 +/- 5.6 vs 17.5 +/- 4.2 cm/s, P = .001). There was no significant difference between the accuracy of this quantitative approach and expert visual wall motion analysis (81% vs 84%, P = .56). Conclusion: Regional variation of uni-dimensional myocardial velocities necessitates site-specific normal ranges, probably because of different fiber directions. Combined analysis of longitudinal and radial velocities allows the derivation of a composite velocity, which is homogenous in all segments and may allow better separation of normal and abnormal myocardium.

Management of a previously eroded tropical Alfisol with herbaceous legumes: Soil loss and physical properties under mound tillage

A study was carried out on a previously eroded Oxic Paleustalf in Ibadan, southwestern Nigeria to determine the extent of soil degradation under mound tillage with some herbaceous legumes and residue management methods. A series of factorial experiments was carried out on 12 existing runoff plots. The study commenced in 1996 after a 5-year natural fallow. Mound tillage was introduced in 1997 till 1999. The legumes - Vigna unguiculata (cowpea), Mucuna pruriens and Pueraria phaseoloides - were intercropped with maize in 1996 and 1998 while yam was planted alone in 1997 and 1999. This paper covers 1997-1999. At the end of each year, residues were either burned or mulched on respective plots. Soil loss, runoff, variations in mound height, bulk density, soil water retention and sorptivity were measured. Cumulative runoff was similar among interactions of legume and residue management in 1997 (57-151 mm) and 1999 (206-397 mm). However, in 1998, cumulative runoff of 95 mm observed for Mucuna-burned residue was significantly greater than the 46 mm observed for cowpea-burned residue and the 39-51 mm observed for mulched residues of cowpea, Mucuna and Pueraria. Cumulative soil loss of 7.6 Mg ha(-1) observed for Mucuna-burned residue in 1997 was significantly greater than those for Pueraria-mulched (0.9 Mg ha(-1)) and Mucuna-mulched (1.4 Mg ha(-1)) residues whereas in 1999 it was similar to soil loss from cowpea treatments and Pueraria-burned residue (2.3-5.3 Mg ha(-1)). There were no significant differences in soil loss in 1998 (1-3.2 Mg ha(-1)) whereas Mucuna-burned residue had a greater soil loss (28.6 Mg ha(-1)) than mulched cowpea (6.9 Mg ha(-1)) and Pueraria (5.4 Ms ha(-1)). Mound heights (23 cm average) decreased non-linearly with cumulative rainfall. A cumulative rainfall of 500 mm removed 0.3-2.3 cm of soil from mounds in 1997, 3.5-6.9 cm in 1998 and 2.3-4.6 cm in 1999, indicating that (detached but less transported) soil from mounds was far higher than observed soil loss in each year. Soil water retention was improved at potentials ranging from -1 to -1500 kPa by Mucuna-mulched residue compared to the various burned-residue treatments. Also, mound sorptivity at -1 cm water head (14.3 cm h(-1/2)) was higher than furrow sorptivity (8.5 cm h(-1/2)), indicating differences in hydraulic characteristics between mound and furrow. Pueraria-mulched residues for mounds had the highest sorptivity of 17.24 cm h(-1/2), whereas the least value of 6.96 cm h(-1/2) was observed in furrow of Mucuna-burned residue. Pueraria phas eoloides was considered the best option for soil conservation on the previously eroded soil, cultivated with mound tillage. (c) 2005 Elsevier B.V. All rights reserved.

Validity of (-)-[H-3]-CGP 12177A as a radioligand for the 'putative beta(4)-adrenoceptor' in rat atrium

1 We have recently suggested the existence in the heart of a 'putative beta(4)-adrenoceptor' based on the cardiostimulant effects of non-conventional partial agonists, compounds that cause cardiostimulant effects at greater concentrations than those required to block beta(1)- and Bz-adrenoceptors. We sought to obtain further evidence by establishing and validating a radioligand binding assay for this receptor with (-)-[H-3]-CGP 12177A ((-)-4-(3-tertiarybutylamino-2-hydroxypropoxy) benzimidazol-2-one) in rat atrium. We investigated (-)-[H-3]-CGP 12177A for this purpose for two reasons, because it is a nonconventional partial agonist and also because it is a hydrophilic radioligand. 2 Increasing concentrations of(-)-[H-3]-CGP 12177A, in the absence or presence of 20 mu M (-)-CGP 12177A to define non-specific binding, resulted in a biphasic saturation isotherm. Low concentrations bound to beta(1)- and beta(2)-adrenoceptors (pK(D) 9.4+/-0.1, B-max 26.9+/-3.1 fmol mg(-1) protein) and higher concentrations bound to the 'putative beta(4)-adrenoceptor' (pK(D) 7.5+/-0.1, B-max 47.7+/-4.9 fmol mg(-1) protein). In other experiments designed to exclude beta(1)- and beta(2)-adrenoceptors, (-)-[H-3]-CGP 12177A (1-200 nM) binding in the presence of 500 nM (-)-propranolol was also saturable (pK(D) 7.6+/-0.1, B-max 50.8+/-7.4 fmol mg(-1) protein). 3 The non-conventional partial agonists (-)-CGP 12177A (pK(i) 7.3+/-0.2), (+/-)-cyanopindolol (pK(i) 7.6+/-0.2), (-)-pindolol (pK(i) 6.6+/-0.1) and (+)-carazolol (pk(i), 7.2+/-0.2) and the antagonist (-)-bupranolol (pK(i) 6.6+/-0.2), all competed for (-)-[H-3]-CGP 12177A binding in the presence of 500 nM (-)-propranolol at the 'putative beta(4)-adrenoceptor', with affinities closely similar to potencies and affinities determined in organ bath studies. 4 The catecholamines competed with (-)-[H-3]-CGP 12177A at the 'putative beta(4)-adrenoceptor' in a stereoselective manner, (-)-noradrenaline (pK(iH) 6.3 +/- 0.3, pK(i), 3.5 +/- 0.1), (-)-adrenaline (pK(iH) 6.5 +/- 0.2, pK(iL) 2.9 +/- 0.1), (-)-isoprenaline (pK(iH) 6.2 +/- 0.5, pK(iL) 3.3 +/- 0.1), (+)-isoprenaline (pK(i) < 1.7), (-)-R0363 ((-)-(1-(3,4-dimethoxyphenethylamino)-3-(3,4-dihydroxyphenoxy)-2-propranol)oxalate, pK(i) 5.5 +/- 0.1). 5 The inclusion of guanosine 5-triphosphate (GTP 0.1 mM) had no effect on binding of (-)-CGP 12177A or (-)-isoprenaline to the 'putative beta(4)-adrenoceptor'. In competition binding studies, (-)-CGP 12177A competed with (-)-[H-3]-CGP 12177A for one receptor state in the absence (pK(i) 7.3 +/- 0.2) or presence of GTP (pK(i) 7.3 +/- 0.2). (-)-Isoprenaline competed with (-)-[H-3]-CGP 12177A for two states in the absence (pK(iH) 6.6 +/- 0.3, pK(iL) 3.5 +/- 0.1; % H 25 +/- 7) or presence of GTP (pK(iH) 6.2 +/- 0.5, pK(iL) 3.4 +/- 0.1; % H 37 +/- 6). In contrast, at beta(1)-adrenoceptors, GTP stabilized the low affinity state of the receptor for (-)-isoprenaline. 6 The specificity of binding to the 'putative beta(4)-adrenoceptor' was tested with compounds active at other receptors. High concentrations of the beta(4)-adrenoceptor agonists, BRL 37344 ((RR + SS)[4-[2-[[2-(3-chlorophenyl)-2-hydroxy -ethyl]amino]propyl]phenoxy]acetic acid, 6 mu M), SR 58611A (ethyl((7S)-7-[(2R)-2-(3-chlorophenyl)-2-hydroxyethylamino]-5,6,7,8-tetrahydronaphtyl-2-yloxy) acetate hydrochloride, 6 mu M), ZD 2079 ((+/-)-1-phenyl-2-(2-4-carboxymethylphenoxy)-ethylamino)ethan-1-ol, 60 mu M), CL 316243 (disodium (R,R)-5-[2-[2-(3-chlorophenyl)-2-hydroxyethyl-amino]propyl]- 1,3-benzodioxole-2,2-dicarboxylate, 60 mu M) and antagonist SR 59230A (3-(2-ethylphenoxy)-1-[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-2S-2-propanol oxalate, 6 mu M) caused less than 22% inhibition of (-)-[H-3]-CGP 12177A binding in the presence of 500 nM (-)-propranolol. Histamine (1 mM), atropine (1 mu M), phentolamine (10 mu M), 5-HT(100 mu M) and the 5-HT4 receptor antagonist SE 207710 ((1-butyl-4-piperidinyl)-methyl 8-amino-7-iodo-1 ,4-benzodioxan-5-carboxylate, 10 nM) caused less than 26% inhibition of binding. 7 Non-conventional partial agonists, the antagonist (-)-bupranolol and catecholamines all competed for (-)-[H-3]-CGP 12177A binding in the absence of (-)-propranolol at beta(1)-adrenoceptors, with affinities (pK(i)) ranging from 1.6-3.6 log orders greater than at the 'putative beta(4)-adrenoceptor'. 8 We have established and validated a radioligand binding assay in rat atrium for the 'putative beta(4)-adrenoceptor' which is distinct from beta(1)-, beta(2)- and beta(3)-adrenoceptors. The stereoselective interaction with the catecholamines provides further support for the classification of the receptor as 'putative beta(4)-adrenoceptor'.

Effects of (-)-RO363 at human atrial beta-adrenoceptor subtypes, the human cloned beta(3)-adrenoceptor and rodent intestinal beta(3)-adrenoceptors

1 Chronic treatment of patients with beta-blockers causes atrial inotropic hyperresponsiveness through beta(2)-adrenoceptors, 5-HT4 receptors and H-2-receptors but apparently not through beta(1)-adrenoceptors despite data claiming an increased beta(1)-adrenoceptor density from homogenate binding studies. We have addressed the question of beta(1)-adrenoceptor sensitivity by determining the inotropic potency and intrinsic activity of the beta(1)-adrenoceptor selective partial agonist (-)-RO363 and by carrying out both homogenate binding and quantitative beta-adrenoceptor autoradiography in atria obtained from patients treated or not treated with beta-blockers. In the course of the experiments it became apparent that (-)-RO363 also may cause agonistic effects through the third atrial beta-adrenoceptor. To assess whether (-)-RO363 also caused agonistic effects through beta(3)-adrenoceptors we studied its relaxant effects in rat colon and guinea-pig ileum, as well as receptor binding and adenylyl cyclase stimulation of chinese hamster ovary (CHO) cells expressing human beta(3)-adrenoceptors. 2 beta-Adrenoceptors were labelled with (-)-[I-125]-cyanopindolol. The density of both beta(1)- and beta(2)-adrenoceptors was unchanged in the 2 groups, as assessed with both quantitative receptor autoradiography and homogenate binding. The affinities of (-)-RO363 for beta(1)-adrenoceptors (pK(i) = 8.0-7.7) and beta(2)-adrenoceptors (pK(i) = 6.1-5.8) were not significantly different in the two groups. 3 (-)-RO363 increased atrial force with a pEC(50) of 8.2 (beta-blocker treated) and 8.0 (non-beta-blocker treated) and intrinsic activity with respect to (-)-isoprenaline of 0.80 (beta-blocker treated) and 0.54 (non-beta-blocker treated) (P<0.001) and with respect to Ca2+ (7 mM) of 0.65 (beta-blocker treated) and 0.45 (non-beta-blocker treated) (P<0.01). The effects of (-)-RO363 were resistant to antagonism by the beta(2)-adrenoceptor antagonist, ICI 118,551 (50 nM). The effects of 0.3-10 nM (-)-RO363 were antagonized by 3-10 nM of the beta(1)-adrenoceptor selective antagonist CGP 20712A. The effects of 20-1000 nM (-)-RO363 were partially resistant to antagonism by 30-300 nM CGP 20712A. 4 (-)-RO363 relaxed the rat colon, partially precontracted by 30 mM KCl, with an intrinsic activity of 0.97 compared to (-)-isoprenaline. The concentration-effect curve to (-)-RO363 revealed 2 components, one antagonized by (-)-propranolol (200 nM) with pEC(50)=8.5 and fraction 0.66, the other resistant to (-)-propranolol (200 nM) with pEC(50)=5.6 and fraction 0.34 of maximal relaxation. 5 (-)-RO363 relaxed the longitudinal muscle of guinea-pig ileum, precontracted by 0.5 mu M histamine, with intrinsic activity of 1.0 compared to (-)-isoprenaline and through 2 components, one antagonized by (-)-propranolol (200 nM) with pEC(50)=8.7 and fraction 0.67, the other resistant to (-)-propranolol with pEC(50)=4.9 and fraction 0.33 of maximal relaxation. 6 (-)-RO363 stimulated the adenylyl cyclase of CHO cells expressing human beta(3)-adrenoceptors with pEC(50)=5.5 and intrinsic activity 0.74 with respect to (-)-isoprenaline (pEC(50)=5.9). (-)-RO363 competed for binding with [I-125]cyanopindolol at human beta(3)-adrenoceptors transfected into CHO cells with pK(i)=4.5. (-)-Isoprenaline (pk(i)=5.2) and (-)-CGP 12177A (pK(i)=6.1) also competed for binding at human beta(2)-adrenoceptors. 7 We conclude that under conditions used in this study, (-)-RO363 is a potent partial agonist for human beta(1)- and beta(3)-adrenoceptors and appears also to activate the third human atrial beta-adrenoceptor. (-)-RO363 relaxes mammalian gut through both beta(1)- and beta(3)-adrenoceptors. (-)-RO363, used as a beta(1)-adrenoceptor selective tool, confirms previous findings with (-)-noradrenaline that beta(1)-adrenoceptor mediated atrial effects are only slightly enhanced by chronic treatment of patients with beta-blockers. Chronic treatment with beta(1)-adrenoceptor-selective blockers does not significantly increase the density of human atrial beta(1)- and beta(2)-adrenoceptors.

The chemistry of 5-oxodihydroisoxazoles .19. The synthesis and photolysis of N-thioacylisoxazol-5(2H)-ones

5-Oxodihydroisoxazoles react with thiocarbonyl chlorides to afford N-thioacylisoxazol-5(2H)-ones which lose carbon dioxide under photochemical conditions and undergo intramolecular cyclisation of the iminocarbene to afford thiazoles, However, in some cases loss of carbon dioxide is accompanied by loss of sulfur, giving 1,3-oxazin-6-ones.

Hepatocyte [H-3]-palmitate uptake: effect of albumin surface charge modification

The role of plasma proteins on the cellular uptake of lipophilic substrates has perplexed investigators for many years. We tested the hypothesis that an ionic interaction between the protein-ligand complex and hepatocyte surface may be responsible for supplying more ligand to the cell for uptake. The surface-charged groups on albumin were modified to yield proteins having a range of isoelectric points (ALB, ALBs, ALBm, ALBe had values of 4.8-5.0, 4.5-4.7, 3.0-3.5, 8.4-8.6, respectively). [H-3]-Palmitate uptake studies were performed with adult rat hepatocyte suspensions using similar unbound ligand fractions in the presence of the different binding proteins. Mass spectrometry, isoelectric focusing (pI), and heptane : water partitioning were used to determine protein molecular weight, pI, and protein-palmitate equilibrium binding constant, respectively. Hepatocyte [H-3]-palmitate clearance in the presence of ALBs and ALBm were significantly lower (p < 0.05) than ALB, whereas [H-3]-palmitate clearance in the presence of ALBe was significantly higher (p < 0.05) than ALB. The data were consistent with the notion that ionic interactions between extracellular protein-ligand complexes and the hepatocyte surface facilitate the uptake of long-chain fatty acids.

Early toxicity from preoperative radiotherapy with continuous infusion 5-fluorouracil for resectable adenocarcinoma of the rectum: A phase II trial for the Trans-Tasman Radiation Oncology Group

Purpose: To assess the toxicity and the efficacy of preoperative radiotherapy with continuous infusion 5-fluorouracil (5-FU) for locally advanced adenocarcinoma of the rectum. Methods and Materials: Eligible patients had newly diagnosed localized adenocarcinoma of the rectum within 12 cm of the anal verge, Stage T3-4, and were suitable for curative resection. Eighty-two patients were treated with radiotherapy-50.4 Gy in 28 fractions in 5.6 weeks, given concurrently with continuous infusion 5-FU, using either 96-h/week infusion at 300 mg/m(2)/day or 7-days/week infusion at 225 mg/m(2)/day. Results: The median age was 59 years (range, 27-87), and 67% of patients were male. Pretreatment stages of the rectal cancer were T3, 89% and resectable T4, 11%, with endorectal ultrasound confirmation in 67% of patients. Grade 3 acute toxicity occurred in 5 of 82 patients (6%; 95% confidence interval [CI], 2-14%). Types of surgical resection were anterior resection, 61%; abdominoperineal resection, 35%; and other procedures, 4%. There was no operative mortality. Anastomotic leakage after low anterior resection occurred in 3 of 50 patients (6%; 95% CI, 1-17%). The pathologic complete response rate was 16% (95% CI, 9-26%). Pathologic Stages T2 or less occurred in 51%. Conclusion: Preoperative radiotherapy with continuous infusion 5-FU for locally advanced rectal cancer is a safe regimen, with a significant downstaging effect. It does not seem to lead to a significant increase in serious surgical complications. (C) 2001 Elsevier Science Inc.