[Anti-arrhythmic actions of amidinohydrazone substituted benzophenones. 7. Synthesis of C14 labeled (Z)- and (E)-2-amino-5-chlorbenzophenonamidinohydrazone].
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Biomedical subjects
Publications and source records attributed to P H Richter.
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1. The first example of a P450-dependent N-hydroxylation of an aminoguanidine (amidinohydrazone) is reported for 2-amino-5-chlorobenzophenone amidinohydrazone 1 (G 256) as substrate. 2. The N-hydroxylated metabolite 2 (2-amino-5-chlorobenzophenone N-hydroxyamidinohydrazone NOH-G256) and a further metabolite of 1, the phenol 3, were identified by tlc and ms analysis. 3. The microsomal reduction of an N-hydroxyaminoguanidine (N-hydroxy-amidino-hydrazone) was also demonstrated for the transformation of 2 to 1. 4. Both the N-hydroxylation of the aminoguanidine and the retroreduction of the N-hydroxyaminoguanidine were characterized by quantitative hplc analysis. 5. The conversion of the aminoguanidine 1 to N-hydroxyaminoguanidine 2 may be considered as an analogue of the physiological N-hydroxylation of arginine to N-hydroxyarginine by NO synthases.
The combination of lyophilized G 256 and a solvent ampoule is recommended as an optimal variant for the application of the compound. In the lyophilized substance both the hydrolysis and the isomerisation are reduced so it is stable enough for the required period of usability.
The aqueous solution of the title compound can be used for injection for one year if it is stored at room temperature and under light protection. Under these conditions 8% of the E-isomer are produced. The reaction is reversible at day light. Red coloured products of decomposition are formed by long lasting influence of light. At higher temperatures or at sterilisation several products of decomposition are formed which structure is elucidated. For these decomposition a scheme is proposed.
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The isomerization of the title compound in a preparative scale can be realized by acetylation/deacetylation or by influence of protons in dimethylformamide. The title compound is obtained als main product of the condensation of 2-amino-5-chlorbenzophenone and aminoguanidine if the reaction is carried out in the presence of formaldehyde.
The title compounds undergo a photoisomerization by irradiation. If the E-isomers are irradiated by light of a wavelength of an absorption maximum typical for them, they can be converted quantitatively to the corresponding Z-isomers. In case that the synthesis of analogs of the title compounds give only one configurational isomer, sometimes the missing one can be obtained by photoisomerization.
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The title compounds are synthesized as a rule by condensation of substituted benzophenones and derivatives of aminoguanidine in the presence of up to 2.5 moles of an anorganic acid. They can be obtained alternatively via corresponding hydrazones, thiosemicarbazones or methylthiothiocarbonylhydrazones.
The configurational isomers of the 2-amino-5-chlorbenzophenoneamidinohydrazones could be obtained as TLC pure samples by fractionating crystallization of the product mixture. The determination of their configuration by comparison of the UV spectra with the corresponding oximes could be confirmed by X-ray structure analysis.
The phenomenon of the wandering point on a blank sheet of paper in serial reproductions is the starting point of an investigation of the perceptual field structure of homogeneous stimulus areas; 609 stimulus points distributed regularly in 21 rows and 29 columns on a DIN A4 sheet were presented successively to 10 subjects and had to be reproduced immediately afterwards in order to establish empirical vector fields. These were subjected to vector-analytic procedures. A method for the decomposition of the measured vector fields into partitions from gradient potentials and circulation potentials is demonstrated. The gradient potentials of the empirical vector fields revealed a highly regular structure with four point attractors near the corners of the sheet. A model calculation of the wandering point in this potential landscape showed results comparable to the empirical phenomenon. The results are discussed in favor of Gestalt theory and against direct perception.
Some title compounds can be obtained conveniently by dehydration of 2-acylhydrazino- or by dehydrogenation of 2-(2-methylenhydrazino)- or by elimination of aniline from 2-phenyl(thio)semicarbazido-1,3,4-benzotriazepines. The direct cyclization of 2-hydrazino-1,3,4-benzotriazepines is not so suitable. The direction of the anellation can be elucidated by comparison of the UV spectra from compounds of known structure.
The oscillations observed in glycolysis are analyzed from the point of view of efficiency of free energy conversion. It is suggested that the mechanisms generating these oscillations may have evolved in order to reduce the dissipation of free energy.
We suggest that temporal oscillations of concentrations of intermediates in biochemical reaction systems may enhance the efficiency of free energy conversion (reduce dissipation) in those reactions. Experiments on glycolysis are used to estimate the Gibbs free energy changes along the glycolysis mechanism, and to postulate a construct for the glycolysis "machine" which involves: the PFK reaction as the primary oscillophor; the GAPDH reaction as a phase-shifting device; and the PK reaction with the property of intrinsic oscillatory response at resonance with the driving frequency. Analysis of a simple reaction mechanism with these postulated properties shows that the conversion of free energy from reactants to products is more efficient in an oscillatory than a steady state operation. The efficiency of free energy conversion in glycolysis from glucose + ADP to products + ATP is estimated to be increased by 5--10% due to oscillations. This may have been relevant for the evolutionary development of oscillations such as in glycolysis, especially in anaerobic cells.
Association rates are calculated for cases where one reaction partner belongs to a chain that has an unspecific affinity to the other. Provided that the unspecific attachment does not completely suppress diffusion along the chain, this channeling may considerably speed up the association. Explicit formulae are derived to show how this effect depends on the chain length and other parameters. The influence of electrostatic forces and reaction barriers is discussed. Time dependent solutions of the diffusion equations are analyzed in order to test the usual steady state assumptions. Experiments on the repressor-operator system seem to be in good agreement with our theory.
The fact that every antibody also has antigenic properties leads to the existence of a functional network of interacting antibodies and lymphocytes in the immune system. With a minimum set of assumptions about the nature of these interactions some of the principal features of the immune response such as normal primary and secondary response, low and high zone tolerance induction, and memory can be reproduced. The low zone tolerance phenomenon plays a central role in our theory, as it is the simplest nontrivial mode of response to an antigenic stimulus. It may be understood as the defeat of the stimulated lymphocyte species against their internal adversaries. The normal response and high zone tolerance induction may be characterized as low zone tolerance on a second and third level of a hierarchy of lymphocyte populations. In particular, the weakness of the primary response is explained in terms of internal struggles which lead to a final suppression of the aggressors, thereby opening the way for an unhindered secondary response.
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