Chemical Model Systems Research Articles

Substituent Constant for Drug Design Studies Based on Properties of Organic Electron Donor–Acceptor Complexes

A new model chemical system based on organic electron donor–acceptor complexes is described. From values of equilibrium constants measured by an NMR technique, a predictable parameter for use in quantitative structure–activity relationship techniques is discussed.

Collective quantum states in model chemical systems

Phenomenological field equations that describe isothermal chemical kinetics are cast into Hamiltonian form. The formalism is applied to a model reaction with autocatalytic chemicals in an extensive solution of substrate. Transforming the Hamiltonian into a collective representation shows that the autocatalytic subsystem can exist as a localized object with a discrete negative energy spectrum. It is observed that the collective state of matter exemplified by the model system also applies to other hypothetical reactions.

Chaos in an enzyme reaction

Dynamic systems are usually thought to have either monotonic or periodic behaviour. Although the possibility of other types of behaviour has been recognised for many years, the existence of non-monotonic, non-periodic behaviour in dynamic systems has been firmly established only recently. It is termed chaotic behaviour. A review on the rapidly expanding literature on chaos in discrete model systems described by difference equations has been published by May. Rössler, on the other hand, has discussed a few published works on systems of differential equations with chaotic solutions, and he has proposed a three-component chemical model system which he argues has chaotic solutions [figure see text]. The argument is based on a theorem by Li and Yorke. Here we report the finding of chaotic behaviour as an experimental result in an enzyme system (peroxidase). Like Rössler we base our identification of chaos on the theorem by Li and Yorke.

Crystal chemistry of the scheelite solid solutions in the systems SrMO 4Eu 2(MO 4) 3 and EuMO 4Eu 2(MO 4) 3 (M = Mo, W)

It is proposed in this study that the Sr 2+Eu 2+ crystal chemical analogy can be used to study phase equilibria in portions of EuMO systems which often present experimental difficulties by studying instead SrMO phase relations. To test this proposition phase relations in the 1050°C isotherm of the proposed model systems SrMO 4Eu 2(MO 4) 3 and EuMO 4Eu 2(MO 4) 3 (M = Mo, W) have been investigated. The composition limits of two solid solution phases, one with a scheelite structure type and the other with a scheelite related structure, and the two-phase regions in each of the systems have been determined and compared, yielding a good correlation between the crystal chemical model systems SrMO 4Eu 2(MO 4) 3 and their pure europium counterparts. The defect model of the scheelite solid solutions has been determined to be a cation vacancy type and confirmed by density measurements.

A mechanistic study of aromatic hydroxylamine rearrangement in the rat

A modified crossover experiment was conducted to determine the mechanism of arylhydroxylamine rearrangement in the rat. When 1-hydroxy-1-phenyl-3-methylurea was incubated with fractionated liver homogenates or injected intraperitoneally in rats, 1-methylbenzimidazol-2-one was isolated as the major metabolite. Small amounts of the anticipated aminophenol, 1-( o-hydroxylphenyl)-3-methylurea were also isolated. Evidence is presented suggesting that hepatic isomerase-catalyzed rearrangements of hydroxylamines proceed via pathways analogous to those described for chemical model systems. Isomerization appears to be intermolecular involving the generation of a resonance-stabilized nitrenium ion capable of binding to amino acids and nucleotide bases.

The Conversion of 2-Hydroxyethylhydrazine to Ethylene

It was shown that 2-hydroxyethylhydrazine is a source of ethylene in a chemical model system. Treatment of pea seedlings produces physiological responses similar to that of ethylene. The hypothesis is advanced that 2-hydroxyethylhydrazine effects this response in pea seedlings via the release of ethylene, as was suggested earlier for its effect on abscission and flowering.

The NIH shift during the hydroxylation of aromatic substrates by fungi

The migration and retention of deuterium which occurs during aromatic hydroxylation of several substrates (NIH Shift) with a range of fungi is compared to the migration and retention obtained with liver microsomes and a chemical model system; enzymatic mechanisms are discussed in terms of arene oxide intermediates.

Indirect Radioprotection by Sulfhydryl Compounds: A Model Chemical System

It is shown that radicals produced from ethanol, formate, and methanol by OH radical attack are able to destroy the thymine chromophore, with a rate constant of the order of $10^{5} M^{-1}\,{\rm sec}^{-1}$ . Addition of small quantities of cysteine protects thymine almost completely. This is explained by H-atom transfer from the sulfhydryl compound to the organic radical thus restoring the parent organic molecule and preventing the reaction of the organic radical with thymine. It is suggested that this type of indirect protection of a DNA constituent may be of importance for the radioprotection of DNA in living cells.

Radiosensitization by N-ethyl maleimide--a model chemical system.

SummaryN-ethyl maleimide (NEM) a known cellular radiosensitizer was studied from a radiation chemical viewpoint. It was found to react rapidly with water free radicals. The NEM-OH radical adduct can react further with another NEM molecule in the absence of oxygen. NEM also reacts with radicals produced by the reactions of OH free radicals and hydrated electrons with nucleic acid components. These reactions occur in the absence of oxygen by both electron transfer and bond formation. NEM is able to compete with oxygen for free radicals produced by reaction of OH + thymine. These oxygen-like reactions of NEM may explain in part the mode of action of NEM as a radiosensitizer at the cellular level.

Nonenzymic, Polyvalent Anion-catalyzed Formation of Methylglyoxal as an Explanation of Its Presence in Physiological Systems

Abstract The long standing question of the source of methylglyoxal formed in glycolyzing tissues was considered. Nonbiological studies, made with chemical model systems, made evident that the formation of methylglyoxal from dihydroxyacetone and from dl-glyceraldehyde under physiological conditions of pH and temperature is catalyzed by Tris and by certain polyvalent anions including phytate, phosphate, tetraborate, arsenate, arsenite, cacodylate, α,β-glycerophosphate, glucose 6-phosphate, fructose 6-phosphate, and fructose 1,6-diphosphate. Borate and bicarbonate also catalyze the reaction at higher pH values. Methylglyoxal does not accumulate in the presence of other inorganic polyvalent anions, adenosine triphosphate, pyrophosphate, amino acids, polyvalent organic acids, monovalent anions or cations, polyvalent cations, or bovine albumin. The reaction between trioses and phosphate appears to follow second order kinetics. The second order rate constant, k2, is estimated to be 1.2 x 10-3 mm-1 hr-1 for dihydroxyacetone, and 6 x 10-4 mm-1 hr-1 for glyceraldehyde. The half-life period of the reaction between triose and phosphate ion may be estimated from the equation, t½ = ln2/k2[A], where [A] is the phosphate concentration (mm). The results are considered to be a possible explanation of many published observations of the appearance of methylglyoxal in glycolyzing tissues. The potential for methylglyoxal formation in biological tissues and in certain buffer systems possibly has wide ranging metabolic implications.

Enzymic 6-hydroxylation of indolealkylamines and related compounds

Further studies on the liver microsomal 6-hydroxylation of lipid-soluble 3-substituted indoles demonstrate that the responsible enzyme system possesses many features in common with the microsomal drug metabolizing enzymes. However, the hydroxylation is not inhibited by bipyridyl, and animal pretreatment with phenobarbital exerts a weak stimulatory effect on the yield of 6-hydroxy compounds. The enzyme is not highly stereospecific as the d- and l-forms of N-acetyltryptophan are hydroxylated at equal rates. 6-Fluoro and methyl groups are not displaceable by hydroxy groups. Non-enzymatic hydroxylation of indolic substrates by chemical model systems gives rise to more than one monohydroxy product; on the other hand, microsomal hydroxylation produces only the 6-isomer, indicating positional specificity. microsomal hydroxylation produces only the 6-isomer, indicating positional specificity. Comparison with aniline p-hydroxylase shows that the two systems are different. The mechanism of the reaction is discussed.

Transfer function analysis of an oscillatory model chemical system.

Abstract Oscillation occurring in the time course of a particular model reaction system is examined, utilizing the transfer function method of analysis developed in a previous paper. System properties predicted by the analytic technique correspond with those observed in analog computer solutions of the kinetic equations describing the system. The transfer function approach provides kinetic criteria for the existence of oscillation in terms of loop gain and phase shift, and elucidates the relation between oscillation and bistability, or flip-flop behavior. Although formulated to be biologically feasible, the model oscillating system is purely hypothetical, and is presented primarily as a basis for the development of general principles concerning periodicity and instability in complex reaction systems.

The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy.

The sensitivity of tumour cells to X rays has been shown to be about three times as great when irradiated in a well-oxygenated medium as under anoxic conditions. The manner in which sensitivity depends on oxygen tension closely resembles that found by other workers for plant and insect tissues. The sensitivity of the tumour cells to fast neutron radiation is only slightly affected by oxygen tension. Consideration is given to the supply of oxygen to tissues as a factor in radiotherapy, and it is concluded on the basis of existing knowledge that in certain circumstances the effectiveness of X-ray treatment might be increased if the patient were breathing oxygen at the time of irradiation. The Ehrlich ascites tumour cells used in the in vitro experiments were grown as a solid tumour and exposed to X rays while the mice were inhaling various mixtures of oxygen and nitrogen at 1 atmosphere pressure and above. In all cases, except when the tumour was very large at the time of irradiation, the regression produced by a given dose was greater when the inspired gas was oxygen than when it was air. The effect of oxygen treatment on the response of the tumour was much greater than on that of skin and hair, as would be expected if these tissues are normally well supplied with oxygen. In the most satisfactory experiment so far made, 1000 r administered to mice breathing oxygen at 1 atmosphere produced about the same tumour regression as 1500 r delivered to mice breathing air. Cell degeneration produced by exposing chick fibroblasts to X rays in vitro showed a dependence on oxygen tension of the same general type as the tumour cells and other tissues, but the exact form of this relation between radiosensitivity and oxygen tension remains to be determined. Two chemical model systems have been examined, and in one of them the amount of chemical change produced by a given dose of X rays was found to vary with the concentration of dissolved oxygen in a manner rather closely resembling the biological systems. Reasons are given for believing that oxygen exerts an important influence on biological response by affecting the chemical changes produced directly in the cell by the radiation. We would like to emphasise that these investigations are still only at an early stage, but the information to hand seemed to us to show that the influence of oxygen tension as a factor in radiotherapy merits much fuller investigation. It would not be possible, on the basis of our experiments, to predict that any particular human tumour would respond more favourably to X-ray treatment if the patient were breathing oxygen at the time of irradiation. We believe, however, that the possibility of substantial differential gain in effectiveness of the radiation with respect to tumour tissue relative to well-oxygenated normal tissue is inherent in any situation in which regions of partial anoxia occur in a human tumour.