Biomedical subjects
Publications and source records attributed to C Christophersen.
Two new flavones were isolated from the medicinal plant Calliandra californica, 7,2',4',5'-tetramethoxyflavone [1] and 5-hydroxy-7,2',4',5'-tetramethoxyflavone [2]. The structures were determined from spectral evidence and both compounds were synthesized. Compound 2 exhibited antimicrobial activity for two test bacterial strains.
A novel antibiotic alpha,beta-unsaturated sesquiterpene ketone, albaflavenone with a zizaene skeleton was isolated from a morphologically novel, highly odorous Streptomyces species which was identified with the species group S. albidoflavus, cluster 1. The new compound, partly responsible for the odour, was assigned the structure of 2R',6,7,7-tetramethyl-1S',8R'- tricyclo-[6.2.1.0(1,5)]undec-5-en-4-one based on spectroscopic studies including 2D NMR (COSY, HETCOR, ROESY, NOE-difference) experiments.
The flesh of the Greenland shark, Somniosus microcephalus, especially in fresh condition, is toxic to both dog and man. Analysis of the toxic fractions indicates the presence of large amounts of trimethylamine oxide (TMAO) but no other substances that could be directly responsible for the poisoning. The symptoms appear to be due to an acute trimethylamine (TMA) poisoning arising from intestinal reduction of TMAO to TMA. TMA stimulates contraction of the guinea-pig ileum (antagonized by atropine but not hexamethonium). Low concentrations of TMA increase contraction of the rat phrenic nerve-diaphragm preparation, whereas higher concentrations cause blockade.
1. A hypothesis is advanced to the effect that all metabolites, even minor ones, are expressed as a result of stimuli and are directed against or support actions on receptor systems. 2. In particular the hypothesis emphasizes the dynamic character of the secondary metabolite pattern as a function of physiological or environmental conditions and that the variations observed reflect the evolution of receptors. 3. Predictions based on this principle are experimentally verifiable. 4. The hypothesis has major implications in the entire area of life sciences.
The medicinal plant Lepechinia hastata, used as a remedy against uterine infections in Baja California Sur (Mexico), was shown to contain carnosol as the main diterpenoid secondary metabolite. Carnosol has potent in vitro antimicrobial activity. Detailed spectroscopical properties of carnosol are presented.
The occurrence of tetramethylammonium ion (TMA) in marine organisms is reviewed. The pharmacological action of TMA is also discussed, with special emphasis on the sign and symptoms experienced by oral poisonings. It is concluded that the major manifestations of TMA poisonings may be attributed to interactions with the autonomous nervous system. Fatal intoxications are due to neuromuscular blockade.
The chemical nature of extracts of the marine gastropod Neptunea antiqua collected in the North Sea has been investigated. Amino acid analysis and spectroscopical studies (FAB MS, 1H NMR, 13C NMR and IR) on fractions purified by Biogel P-2 and Amberlite IR 120 column chromatography allowed the identification of 19 components. It was established that the water-soluble toxin responsible for poisonings, following ingestion of this snail, is tetramine (the tetramethylammonium ion present as an unknown salt). Contrary to what occurs in other Neptunea species (N. arthritica and N. intersculpta), tetramine was found not only in the salivary gland, but also in the remaining part of the animal, albeit in smaller concentration. In the isolated guinea-pig ileum assay, synergistic effects with other main components present (betaine, homarine) could not be demonstrated. Choline esters, believed to act synergistically in other Neptunea species, were not detected in Neptunea antiqua.
Five ammonium compounds--betaine, taurine, homarine, trigonelline and tetramethylammonium chloride--were investigated by positive and negative ion fast atom bombardment (FAB) mass spectrometry. Observation of the parent cation [M + H]+ together with series of clusters (e.g. [nM + H]+, n = 2-5) and fragmentation patterns in the positive FAB mode may be used diagnostically as a fingerprint of the compound. The shifts in mass and relative intensity by addition of trichloroacetic acid and metal salts offer corroborating information of the identity of a compound in a mixture. The FAB negative ion spectra were characterized by clusters incorporating the anion (e.g. [M + Cl]-) but are generally less informative than the spectra obtained in the positive mode.
The phenylhydrazone of N-[D-fructosyl-(1)]-L-valine (1-deoxy-L-valine-D-fructose) was synthesized. The hydrazone was shown to exist in open form in basic solution and in closed form in acidic solution. The findings have bearings upon the discussion of the reaction of human haemoglobin A1c with phenylhydrazine.
Secondary metabolites from marine bryozoans are reviewed. Two ctenosome bryozoans are dealt with, one, Alcyonidium gelatinosum containing a sulfoxonium ion acting as hapten in an allergic contact dermatitis and the other, Zoobotryon verticillatum yielding bromogramines. Five cheilostome bryozoans have given rise to the isolation of unique secondary natural products. Bugula neritina is the source of the antineoplastic bryostatins and Bugula purple while Flustra foliacea have yielded an array of bromoindole alkaloids and a brominated quinoline. Chartella papyracea also have bromoindole alkaloids while Sessibugula translucens have ecological active bipyrroles. A biological active xanthine derivative has been reported from Phidolopora pacifica. The structure and chemistry of these compounds are discussed as are their origin, function and biological activity.
The reaction kinetics for the reversible condensation of D-glucose and haemoglobin A through a labile haemoglobin A-aldimine adduct to HbA1c have been investigated using a biokinetic model. The specific rate constants obtained from in vitro experiments were included in the model which also took into account the removal of HbA1c by decay of erythrocytes. Using a sinusoidal variation in blood glucose a phase delay of about 2 hours was observed between the maximum blood glucose concentration and the maximum aldimine concentration. The mean haemoglobin A-aldimine concentration was independent of both the amplitude and frequency of the blood glucose oscillations and reached equilibrium concentration within 24 hours. The steady state relation between mean blood glucose and HbA1c was similar to the corresponding relation based on an irreversible formation of HbA1c. However, contrary to the irreversible model the steady state HbA1c concentration with the reversible model was reached 3 to 4 weeks after a change in blood glucose level. This finding is in agreement with clinical experience and indicates that in assessing continuous glycaemic control in diabetic patients haemoglobin A1c should be measured approximately every 3 to 4 weeks.
We examined the stability of the ketoamine adduct, termed HbA1c, formed between the N-terminal valine of the haemoglobin A (HbA) beta chain and D-glucose using an isoelectric focusing method. Prolonged saline incubation of purified HbA1c followed by renewed isoelectric focusing revealed that the HbA1c concentration decreased while a corresponding increase in the HbA concentration occurred. The emergence of haemoglobin A on saline incubation indicates that the non-enzymatic glucosylation of haemoglobin A to HbA1c is a reversible process. This finding was further substantiated by kinetic studies on the formation and breakdown of the ketoamine adduct during incubation of red cells in glucose and saline. It appeared that the rate constant for the formation k2 was 14.2 X 10(-6) X s-1 at 37 degrees C while the rate constant for dissociation k-2 was 1.7 X 10(-6) X s-1. From these data an equilibrium constant K of 8.4 was calculated. This information should be of importance in interpretation of HbA1c levels during abrupt changes in diabetic control.
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The reaction between glucose and hemoglobin A (HbA) leading to hemoglobin A1c through a labile intermediate, designated anodal glycohemoglobin A, was studied in vitro using an isoelectric focusing method. Studies were performed on the kinetics of the formation and breakdown of the labile intermediate. The reactions of HbA with various aldohexoses and of hemoglobin A1c and anodal glycohemoglobin A with phenylhydrazine were studied. It is suggested that the glucose in the anodal glycohemoglobin A band is in the pyranose form of a Schiff base formed between the N-terminal amino group of the protein and D-glucose, while the fructose in hemoglobin A1c is in the pyranose form of the ketimine comprising also the N-terminal of the group. Elution peaks from ion-exchange chromatography of the hemoglobins termed HbA1a, HbA1b, HbA1c and HbA studied by isoelectric focusing revealed that: HbA1a formed two bands and HbA1b one band far toward the anode; both contained minor fractions of HbAlc and HbA; HbAlc appeared as a single band, while HbA was contaminated with some HbA1c. Hemoglobulin A1c purified by isoelectric focusing eluted as one peak when analysed by ion-exchange chromatography, while anodal glycohemoglobin A co-eluted with the first HbA1c fractions in the chromatogram. From kinetic studies it appeared that the rate constant for formation (k1) of anodal glycohemoglobin A was 0.096 . 10(-3) l/mol . s-1 at 37 degrees C. The constant for dissociation (k-1) was 0.10 . 10(-3) s-1. From these an equilibrium constant K of 0.96 l/mol was calculated. The apparent Arrhenius activation energies for the (k1) and (k-1) reactions were 42.5 and 47.5 kJ/degree, respectively. Consequently the equilibrium constant K is predicted to be nearly temperature-independent within the temperature range investigated. This was fully substantiated by experiments conducted at different temperatures. Furthermore, the values of the apparent Arrhenius activation energies allows the values of the rate constants to be calculated at any temperature within the experimental temperature range. This information is of importance for a closer understanding of the mechanisms of glycohemoglobin accumulation in red blood cells.
Repeated exposure to the marine bryozoan, Alcyonidium gelatinosum, frequently provokes an eczematous allergic contact dermatitis known as the "Dogger Bank Itch". The dermatitis, representing a severe occupational disease, is especially widely distributed among trawlermen working in the Dogger Bank area in the North Sea. The allergy is shown to belong to the type of cell-mediated hypersensitivity. The hapten has been identified as the (2-hydroxyethyl)dimethylsulfoxonium ion. The isolation, structure determination and synthesis are discussed.
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The crystal and molecular structure of the meso-ionic title compound, C13H10N4O, have been determined by X-ray methods using 2667 reflections above background level collected by counter methods at 105 K. The crystals are monoclinic, space group P2a/c, with cell dimensions: a=5.233(2) A; b=18.846(6) A; c=11.643(2) A, beta=105.71 degrees(2), with 4 molecules per unit cell. The structure model was refined to an R-factor of 0.047. In order to reduce the influence of the valence electrons all reflections with sin theta/lambda smaller than 0.5 A- minus 1 were excluded in the last stages of the refinement procedure (leaving 1658 Fo'S, R=0.058). The central five-membered ring is found to be planar and the bond lengths within this ring indicate a resonance stabilized system, as has been found for sydnones. The planes of the two benzene rings are tilted 11.7 and 8.0 degrees, respectively, with respect to the plane of the central oxatriazolio-ring.?