[The influence of some retarding agents NOS of dihydrothiazine-thiazoline rank on postradiational of recovery endogenous CFU-S-8 of mice].

In this work the attempt to estimate a nitric oxide (NO*) role in regulation of the number of pool haemopoietic stem cells at the irradiated mice was made. With this purpose the number of new compounds from dihydrothiazine-thiazoline line was synthesized, their NO-inhibiting activity was investigated in vivo by the method of ESR-spectroscopy of spin trap and their influence on an output endogenous spleen colonies (CFU-S-8) after the total sublethal y-irradiation of mice in a doze of 6 Gy was also investigated. Was shown, that the tested compounds reduced the contents of NO* in a liver tissue of mice which have received an injection of nitric oxide synthesis inductor - lipopolysaccharide, and also increased an output CFU-S-8 forming endogenous colonies in the spleen of the irradiated mice. Received data testify to perceptivity of search radioprotective agents among NO* synthesis inhibitors.

Structure and activity of NO synthase inhibitors specific to the L-arginine binding site.

Synthesis of compounds containing a fragment similar to the guanidine group of L-arginine, which is a substrate of nitric oxide synthase (NOS), is the main direction in creating NOS inhibitors. The inhibitory effect of such compounds is caused not only by their competition with the substrate for the L-arginine-binding site and/or oxidizing center of the enzyme (heme) but also by interaction with peptide motifs of the enzyme that influence its dimerization, affinity for cofactors, and interaction with associated proteins. Structures, activities, and relative in vitro and in vivo specificities of various NOS inhibitors (amino acid and non-amino acid) with linear or cyclic structure and containing guanidine, amidine, or isothiuronium group are considered. These properties are mainly analyzed by comparison with effects of the inhibitors on the inducible NOS.

Effect of NO synthase inhibitor 2-amino-5,6-dihydro-4H-1,3-thiazine on endotoxin-induced changes in hemodynamic parameters and respiration in rats.

We studied the effect of NO synthase inhibitor 2-amino-5,6-dihydro-4H-1,3-thiazine (2-ADT) on the cardiovascular system in rats with endotoxic shock. Blood pressure, heart rate, and respiratory rate were recorded. E. coli lipopolysaccharide decreased blood pressure and heart rate. 2-ADT in a dose of 5 mg/kg normalized these hemodynamic parameters. The normalizing effect of 2-ADT decreased with increasing the dose of this preparation. 2-ADT in high doses (10, 20, and 30 mg/kg) and repeated injections of the preparation caused death of experimental animals.

[NO-inhibiting activity of radioprotectors]. / NO-ingibiruiushchaia aktivnost' radioprotektorov.

The effect of radioprotectors of different structure on the syntheses of nitric oxide induced by endotoxin in mice was studied. Using ESR-spectroscopy and spin trap techniques, it was shown that compounds of different chemical structure, such as aminothiols, isothiuronium derivatives, thiazolines, indolylalkylamines and others, suppressed the nitric oxide production in a whole body. The analysis of the relevant literature has confirmed the phenomenon described by the authors: radioprotectors show NO-inhibiting activity.

[Study of the antiradical and radioprotective properties of S-containing compounds using the complex of in vitro test-systems]. / Izluchenie antiradikal'nykh i protivoluchevykh svoistv S-soderzhashchikh soedinenii s ispol'zovaniem kompleksa test-sistem in vitro.

Capability of S-radioprotectors (AET, 2-AT, 2-ADT) to react with OH-radicals and to protect various molecular biotest systems against radiation damage was compared with that of 5-methoxytryptamine, some amino acids and t-butanol. A method of competing acceptors was used to determine rate constants in reactions of the radioprotectors with OH-radicals. A complex of biotest systems (protein, DNA, protein-lipid complex) was applied to estimate the radioprotective activity in vitro. It was found that the studied S-compounds are capable of modifying the protective effect as compared to the expectation from the competitive kinetics approach. Both enhancing and lessening of the effect was observed depending on the test system used. The obtained results can be explained by the impact of secondary radicals on the bio-target and/or by the interaction of the S-compounds with the bio-target that altered its radiosensitivity.

NO-inhibiting and vasotropic activity of some compounds with thioamidine group.

Using the method of electron paramagnetic spectroscopy we demonstrated that thiazine-thiazoline compounds and aminoethyl isothiourea containing the thioamidine group inhibit NO production in the liver of endotoxin-treated mice. Injection of these agents to anesthetized rats increased arterial pressure and enhanced respiration rate. This effect probably reflects inhibition of not only inducible, but also the constitutive synthesis of NO by compounds with thioamidine group.

[Toxicity and radiation protective properties of 2(3)-guanidinoalkanethiols: structure-activity]. / Toksichnost' i protivoluchevye svoistva 2(3)-guanidinoalkantiolov: struktura-aktivnost'.

In experiments with mice radioprotective properties and toxicity of 2(3)-guanidinoalkanethiols were investigated by exposure to gamma-irradiation in the dose of 6.4 Gy. The obtained results allow to find an association between radioprotective activity of 2(3)-guanidinoalkanethiol compounds and their structure and toxicity.

[Function of the hematopoietic system in irradiated animals prophylactically administered 2-amino-2-thiazoline]. / Sostoianie krovetvornoi sistemy u obluchennykh zhivotnykh pri profilakticheskom vvedenii 2-amino-2-tiazolina.

The effect of 2-amino-2-thiazoline (2-AT) on radiosensitivity of mice, their haemopoietic system status, and GFUc has been studied. 2-AT was shown to contribute to the survival of an increased number of haemopoietic stem cells, earlier recovery of bone marrow cellularity, and normalization of the spleen weight.

[Radiation-induced binding of 2-amino-5,6-dihydro-1,3-4H-thiazine to DNA]. / O radiatsionno indutsirovannom sviazyvanii 2-amino-5,6-digidro-1,3-4H-tiazina s DNK.

A study was made of the nature of radiation--induced bonds between DNA and 2-amino-5,6-dehydro-4H-thiazine (2-ADT) having a radioprotective action. Using the gelfiltration method and 35S-2-ADT, it was shown that the amount of the radioprotector bound to DNA increased with radiation dose and did not depend on the postirradiation treatment with 3 M LiCl or 3 M urea. No marked binding was noted after mixing the separately exposed DNA and the protector. It is concluded that a covalent linkage of DNA and 2-ADT occurs, upon irradiation, via short-living states of DNA and (or) the protector.

[Reversal of B to A transition in DNA by bis-(20guanidoethyl)disulfide]. / Obrashchenie B--A-perekhoda v DNK bis(2-guanidoetil)disul'fidom.

Transition from B to A form of DNA in water/ethanol solutions is hindered by stoichiometric quantities of a bifunctional cation, bis-(2-guanidoethyl)disulfide (GED). Using the data on the shift and widening of the B--A transition curves in the presence of GED, a value of the order of 10 base pairs has been estimated for the cooperativity length of the B--A transition which agrees well with the values earlier obtained.

[Peculiarities of DNA winding with bifunctional cations]. / Osobennosti zakruchivaniia DNK bifunktsional'nymi kationamn.

Addition of the bifunctional cations, bis(2-aminoethyl) disulphide-cystamine, and bis(2-guanidoethyl) disulphide-GED, into water solution of DNA results in a decrease in magnitude of the positive circular dichroism (CD) band. However, unlike the similar effect due to alcaline ions or ions of ammonium and guanidinium the above effect occurs at much smaller, stoichiometric with phosphates, concentrations of the dications. Another peculiarity of GED is the attaining of a plato region for the curve of the CD change with the rise of GED concentration. Since the decrease in positive band CD is connected with increase in the rotation angle between the base pairs, the observed behavior of the bifunctional cations are supposedly due to peculiarities of their winding action upon DNA helix. Reducing the disulphide bond in the cations gives rise to increase in the DNA positive CD band up to the values inherent to those in the presence of the corresponding monocations. The higher efficiency of the bifunctional cations is thus due to the cationic groups belong to one and the same molecule. Such compounds could thus be considered as a simple model of DNA-protein interaction.