The conformational models of the active site of adenosine deaminase (ADA) and its complexes in the basic state with adenosine and 13 isosteric analogues of the aza, deaza, and azadeaza series were constructed. The optimization of the conformational energy of the active site and the nucleoside bound with it in the complex was achieved in the force field of the whole enzyme (the 1ADD structure was used) within the molecular mechanics model using the AMBER 99 potentials. The stable conformational states of each of the complexes, as well as the optimal conformation of the ADA in the absence of ligand, were determined. It was proved that the conformational state that is close to the structure of the ADA complex with 1-deazaadenosine (1ADD) known from the X-ray study corresponds to one of the local minima of the potential surface. Another, a significantly deeper minimum was determined; it differs from the first minimum by the mutual orientation of side chains of amino acid residues. A similar conformational state is optimal for the ADA active site in the absence of the bound ligand. A qualitative correlation exists between the values of potential energies of the complexes in this conformation and the enzymatic activity of ADA toward the corresponding nucleosides. The dynamics of conformational conversions of the active site after the binding of substrate or its analogues, as well as the possibility of the estimation of the inhibitory properties of nucleosides on the basis of calculations, are discussed.
A series of N,N¢-acylbisazoles were used to synthesize nucleoside-5¢-polyphosphates, with target product yields which were 10 -15% higher than when unsubstituted N,N¢-acylbisazoles were used.The role of nucleoside-5¢-polyphosphate analogs as inhibitors of a variety of ATP-and GTP-dependent enzymes is well known. We studied the possibility of synthesizing nucleoside-5¢-polyphosphates using a series of substituted N,N¢-acylbisazoles. Published reports include descriptions of the successful use of N,N¢-carbonylbisazoles to activate nucleotide phosphate groups. Activated nucleoside-5¢-phosphoimidazolides are used as intermediate compounds in preparing various dinucleoside-5¢,5¢-phosphodiesters, nucleoside diphosphate sugars, and nucleoside-5¢-triphosphates [1,2]. Interest in the synthesis of these compounds persists as a result of studies of their substrate properties for different DNA polymerases of viral, bacterial, and animal origin [3].The aim of the present work was to investigate the relationship between the reactivity of N,N¢-acylbisazoles and the structures of their azole fragments. Studies were performed on, as an example, the synthesis of ribonucleoside-5¢-polyphosphates, i.e., nucleoside-5¢-phosphoazolides, methylene analogs of P 1 ,P 4 -bis-(nucleoside-5¢)tetraphosphates, and nucleoside-5¢-triphosphates, using substituted N,N¢-acylbisazoles, which have not previously been used for this purpose. The general pathway of the synthesis of these compounds is shown in Scheme 1. EXPERIMENTAL SECTIONThe IR spectra of compounds I -V were recorded using an IKS-29 instrument for samples in KBr tablets. The UV spectra of compounds I -V, nucleoside-5¢-triphosphates 310 0091-150X/10/4406-0310
In the course of previous experiments, a technique was developed for the preparation of a copolymer of styrene and α-methylstyrene. This technique is an emulsion polymerization in the initiator of ammonium persulfate in an inert zone of direct current argon. It was found that the best emulsifier is potassium stearate. This substance can be explained by those copolymers that showed the best dielectric performance. In the course of the new experiment, a series of new copolymers of 4-methylstyrene-α-methylstyrene and 4-methoxystyrene-α-methyl-styrene was obtained in the molar ratios of the initial monomers of 8 : 3, 9 : 2 and 10 : 1 for both rows of copolymers. The outputs of the pure product for all compounds accounted for more than 60% in terms of the initial monomers. To further measure the value of the specific volume resistance of the material, films of each newly synthesized copolymer were obtained. Samples of the copolymers were dissolved in methylene chloride and applied to a smooth glass substrate. The choice of this solvent is due to its low toxicity and low boiling point. For the experiment were selected samples with a film thickness of 50 microns. Measurements of the specific volume resistance were carried out at the Research Institute "Girikond" (St. Petersburg) using an Agilent 4339B instrument. The operating voltage was 100 V. The measurement results showed that samples of 4-methoxystyrene-α-methylstyrene copolymer were several orders of magnitude superior to samples of 4-methylstyrene-α-methylstyrene copolymer. Most likely in this case such a difference in the indices of the specific volume resistance of the copolymer films is due to the nature of the functional groups of substituents in the copolymer. From the obtained measurement results it can be seen that the samples containing the methoxy group have a high resistance value compared to the samples containing a methyl group in their structure. In a series of samples of copolymer films, an increase in the specific volume resistivity index is observed with a decrease in the α-methylstyrene content in the copolymer structure. This dependence is observed for copolymers of 4-methylstyrene-α-methylstyrene and for 4-methoxystyrene-α-methylstyrene. The sample of 4-methoxystyrene-α-methylstyrene with a molar ratio of initial monomers of 10 : 1 has the highest value of specific volume resistance among all the obtained samples of copolymer films.
Two new copolymers of 4-methylstyrene and α-methylstyrene were obtained by the emulsion polymerization method according to the previously described and tested method in the course of the experiment in laboratory conditions. The molar ratio of the starting monomers of 4-methylstyrene and α-methylstyrene was 9: 2 and 10: 1, respectively, in each material sample. The structure of the copolymers obtained was confirmed by IR and 1H NMR spectroscopy. Under laboratory conditions, three prototypes of each copolymer film were obtained from the solution. A sample of the copolymer was dissolved in methylene chloride was applied on a smooth glass substrate. After complete evaporation of the solvent, the film was separated from the substrate. The thickness of the films for each copolymer sample was 20, 30, and 50 microns. In the course of further experimentation, these samples were examined for the values of dielectric constant and tangent of dielectric loss angle. The basis of this experiment used a resonant method of measurement. The presented method is based on the variation of conductivity due to a change in the electrical capacitance of the oscillating circuit. In this experiment, the magnitude of the electrical capacitance and the tangent of the dielectric loss angle were measured. Based on the value of the capacitance and the parameters of the film sample to be measured, it is possible to calculate the dielectric constant. From the data obtained it can be seen that with increasing film thickness, dielectric constant values decrease. However, the indicators of the tangent of dielectric loss angle increase. With an increase in the measurement frequency, a slight decrease in the dielectric constant is observed, and the value of the tangent of the dielectric loss angle decreases nonlinearly. In addition, it should be noted that the samples of 4-methylstyrene-α-methylstyrene copolymer films with a molar ratio of starting monomers of 10: 1 have a higher dielectric constant, along with lower values of the dielectric loss tangent. From this it follows that samples with a lower proportion of α-methylstyrene in their structure have better dielectric characteristics compared with their counterparts with a high content of α-methylstyrene.
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