[Glycol and Phosphate Depot Forms of 4- and/or 5-Modified Nucleosides Exhibiting Antibacterial Activity].

Resistance developed to the majority of drugs used to treat infectious diseases warrants the design of new compounds effective against drug-resistant strains of pathogens. Recently, several groups of modified nucleosides have been synthesized and showed significant antibacterial activity in vitro, but their further studies were difficult to undertake because of their low solubility in aqueous solutions. Nevertheless, new compounds, well soluble in water-organic solutions, were synthesized and found to be more effective in inhibiting the growth of Gram-positive bacteria and mycobacteria. The water-soluble forms of modified nucleosides under study were assumed to be their depot forms. To check the assumption, the compounds were tested for hydrolysis in various media and their molecular docking was performed into the active center of the putative target, Mycobacterium tuberculosis flavin-dependent thymidylate synthase ThyX. Computer modelling showed that the water-soluble analogs do not act as ThyX inhibitors, supporting the assumption of their depot nature. The compounds were resistant to chemical hydrolysis but were hydrolyzed when incubated with porcine liver carboxylesterase, human serum, or Staphylococcus aureus 209P. The results demonstrate that the compounds are most likely depot forms of modified nucleosides.

Development of Liposomal Forms of Modified Pyrimidine Nucleosides and Investigation of Their Antibacterial Properties.

Different phosphocholine-cardiolipin-2'-deoxyuridine inclusion complexes were developed, that allowed to compose a water-soluble form of nucleoside analogues with previously defined antituberculosis activity. It was found that the resulting liposomes effectively penetrated to the cells. The increase of cytotoxicity was undoubtedly indicative of accumulation of the nucleoside in the cell culture. The result proved the ability of the liposomes for delivery of the low-soluble compounds to the cells for further investigation of their efficacy. It was shown that treatment of the bacterial cells with the llposomes of the modified nucleosides did not affect the bacterial growth.

[Synthesis and biological properties of α-thymidine 5'-aryl phosphonates].

The interaction of CDI-activated diethyl phosphonoacetate with methyl 4-aminobenzoat or 3,5-difluoromethylphenylamine followed by treatment with Me3SiBr in DMF led to N-aryl aminocarbonylmethyl phosphonates and their ethyl esters. Their coupling with 3'-acetyl-α-thymidine followed by removal of the acetyl groups gave (α-D-thymidine-5'-il) N-[4-(methoxycarbonyl-, aminocarbonyl- and carboxy)phenyl]-aminocarbonylmethyl phosphonates, (α-D-thymidine-5'-il)-[3,5-bis(trifluoromethyl)phenylaminocarbonyl]methyl phosphonate and their ethyl esters. The phosphonates were stable in different conditions, low cytotoxic (in Vero and K562 cells) and were able to penetrate into K562 cells. The only ethyl ester of (α-D-thymidine-5'-il) N-[4-(methoxycarbonyl)phenyl]-aminocarbonylmethyl phosphonate in high concentration (200 µg/mL) inhibited in vitro the growth of laboratory sensitive strain of Mycobacterium tuberculosis H37Rv.

1,2,4-Triazoloazine derivatives as a new type of herpes simplex virus inhibitors.

A new class of inhibitors of herpes simplex virus replication was found. The compounds under study are derived from condensed 1,2,4-triazolo[5,1-c][1,2,4]triazines and 1,2,4-triazolo[1,5-a]pyrimidines, structural analogues of natural nucleic bases. Antiherpetic activity and cytotoxicity of the compounds were studied. The corresponding triphosphates of several active compounds were prepared and tested as inhibitors of DNA synthesis catalyzed by herpes simplex virus polymerase. The potential mechanism of their action is blocking of DNA dependent DNA polymerase, a key enzyme of viral replication.

[Practical use of a methodology for assessing an aerogenic risk to human risk in the substantiation of a control area].

The aerogenic risk to health was assessed in the population living in an area under the influence of an petroleum refinery in order to define the ambient pollution hazard, to identify the leading risk factors and their sources for further development of the most effective managerial decisions to reduce the risk, which comprise the substantiation of the extent of a control area.

[Use of a methodology to assess a risk at the stage of substantiating the choice of a ground area for placing industrial enterprises].

Human health risk was screened at the stage of supporting the choice of a building site for a petroleum refinery. Based on the calculated exposure levels, the risk to the Buguruslan population was characterized under different conditions: without consideration for the impact of the projected enterprise; with consideration for the pollutants contained in the emissions of the projected enterprise; at the border of an apartment block and at that of an estimated control area in five receptor points. The assessment of a human risk has revealed that the industrial enterprise cannot be sited on this territory and the estimated control area is inadequate due to the high carcinogenic and toxic risk from the formed emission of the projected enterprise.

[New furano- and pyrrolo[2,3-d]pyrimidine nucleosides and their 5'-triphosphates: synthesis and biological properties].

Bicyclic furano[2,3-d]pyrimidine ribonucleosides were synthesized by Pd(0)- and CuI-catalyzed coupling of 5-iodouridine with terminal alkynes. The treatment of the resulting nucleosides with ammonia or methylamine solution in aqueous alcohol resulted in pyrrolo- and N(7)-methylpyrrolo[2,3-d]pyrimidine nucleosides. 5'-O-Triphosphates of bicyclic nucleosides were obtained by the treatment of the nucleosides with POCl3 in the presence of a "proton sponge." The 5'-O-triphosphates are not substrates for HCV RNA-dependent RNA polymerase, but are effective substrates for HCV RNA helicase/NTPase and did not inhibit ATP hydrolysis. Only 3-(beta-D-ribofuranosyl)-6-decyl-2,3-dihydrofuro-[2,3-d]pyrimidin-2-one showed a moderate anti-HCV activity in the HCV replicon system and efficiently inhibited replication of bovine viral diarrhea virus (BVDV) in KCT-cells, other compounds being inactive. None of the compounds were cytotoxic within the tested range of concentrations.

[The synthesis and antiherpetic activity of acyclovir phosphonate esters]. / Sintez i antigerpeticheskaia aktivnost' fosfonatnykh éfirov atsiklovira.

Alkyl esters of acyclovir phosphite, alkoxycarbonylphosphonate, ethoxycarbonylmethylphosphonate, and aminocarbonylphosphonate were synthesized. Most of them were shown to inhibit the replication of type 1 herpes simplex virus in Vero cell culture. The stability in phosphate buffer and human blood serum was studied for several of the derivatives. A correlation between the stability and antiviral activity of the synthesized compounds is discussed. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 6; see also http://www.maik.ru.

[Efficacy of 4'-thio-5-ethyl-2'-deoxyuridine (TEDU) and its derivatives in experimental infection in mice caused by herpes simplex virus]. / Izuchenie éffektivnosti 4'-tio-5-étil-2'-deoksiuridina (TEDU) i ego proizvodnykh, vyzvannoi virusom gerpesa prostogo.

It was demonstrated that several 5'-phosphonates of 4'-thio-5-ethyl-2'-deoxyuridine possessed antiviral activity in vitro and in the murine model of herpes simplex virus type 1 infection. It was shown that the derivatives after intraabdominal administration penetrated effectively into the brain tissue. The agents provided statistically significant increase of the average life span, lower virus titre in the brain and lower lethality when compared to the control group of the animals. It is emphasized that the derivatives were less toxic than the original compound.

[Estimating the hazard of toxic exposure of the population living in the area of the Orenburg gas-chemical complex to specific pollutants]. / Otsenka opasnosti toksicheskogo vozdeistviia spetsificheskikh polliutantov na naselenie, prozhivaiushchee v zone Orenburgskogo gazokhimicheskogo kompleksa.

Health anomalies in children are induced by environmental contamination with pollutants specific for this region due to the long-term running of the Orenburg gas-chemical complex. On assessing the health hazard of exposure to non-carcinogenic chemicals, the authors used such variable as the hazard coefficient. Estimations indicated that the hazard coefficient of non-carcinogenic effects was greater than the allowable level with reference to hydrogen sulfide in all areas under study, as shown by the data of stationary posts. According to the data of route studies, the hazard coefficient exceeded 1 with reference to hydrogen sulfide and nitrogen dioxide. Thus, upon exposure to specific air pollutants, such hydrogen sulfide and nitrogen dioxide, even at the concentrations below the maximum allowable concentration there is an increased hazard of their toxic effect on the population.

[Hygienic assessment of ambient air pollution in rural localities in the area exposed to effluents of the Orenburg gas-field complex]. / Gigienicheskaia otsenka zagriazneniia atmosfernogo vozdukha sel'skikh naselennykh punktov v zone vliianiia vybrosa Orenburgskogo gazopromyslovogo upravleniia.

A complex analysis suggests that there has been an increase in airogenic load on the population living in an area exposed to gas waste from the Orenburg gas-field complex at the expense of nitrogen dioxide, which may be associated with its higher levels in the waste from 1058.3 tons/year in 1996 to 2084.89 tons/year in 2000 and with the maximum effluent of 2550.79 tons/year in 1999. The study has revealed that the rural locality with the greatest aerogenic load is the village of Dedurovka.

[4'-Thio-5-ethyl-2'-deoxyuridine 5'-phosphonates: synthesis and antiviral activity]. / 5'-Fosfonaty 4'-tio-5-étil-2'-dezoksiuridina: sintez i antivirusnye svoistva.

A number of new 5'-phosphonate derivatives of 4'-thio-5-ethyl-2'-deoxyuridine (TEDU) were synthesized. These compounds displayed a low cytotoxicity and, except for TEDU 5'-fluorophosphate, antiherpes activity similar to that of 9-[(2-hydroxyethoxy)methyl]guanine (acyclovir) and 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (pencyclovir). 5'-Ethoxycarbonylphosphonate and 5'-aminocarbonylphosphonate of TEDU were also found to suppress the reproduction of herpes simplex type 1 virus, which is resistant to acyclovir.

Anti-HIV activity of novel phosphonate derivatives of AZT, d4T, and ddA.

Anti-HIV activity and cytotoxicity were tested for novel phosphonate derivatives of AZT, d4T and ddA. For d4T phosphonate derivatives the most active was 2',3'-Dideoxy-2',3'-didehydrothymidine 5'-isopropylphosphite and among the AZT phosphonate derivatives highest activity was shown by 2',3'-Dideoxy-3'-azidothymidine 5'-cyclohexylphosphite.

P-(alkyl)-nucleoside 5'-hydrogenphosphonates as depot forms of antiviral nucleotide analogues.

P-(Alkyl)esters of AZT 5'-hydrogenphosphonate were synthesized and their stabilities in the phosphate buffer and human serum were evaluated. The esters bearing residues of primary and secondary alcohols were degraded to give AZT, whereas those containing tertiary alkyl groups yielded AZT 5'-hydrogenphosphonate. The corresponding derivatives of d2A and d4T showed the same properties.

[Hygienic assessment of physical and psychophysiologic development of children residing in the area of emissions of Orenburg gas-producing plants]. / Gigienicheskaia otsenka fizicheskogo i psikhofiziologicheskogo razvitiia detei, prozhivaiushchikh v zone vybrosov Orenburgskogo gazopromyslovogo upravleniia.

The children and adolescents residing in rural settlements located in the vicinity of sites of industrial extraction and processing of hydrogen sulphide-containing gas were studied. The drinking water and ambient air in these settlements were shown to be polluted. Low indices of the children's mental, physiological, and physical development were revealed.

[Comprehensive hygienic assessment of environmental pollution in rural localities in the area affected by the Orenburg gas processing plant]. / Kompleksnaia gigienicheskaia otsenka zagriazneniia okruzhaiushchei sredy sel'skikh naselennykh punktov v zone vliianiia Orenburgskogo gazopererabatyvaiushchego zavoda.

Comprehensive analysis of environmental pollution was made in 15 rural settlements of Orenburgsky and Perevolotsky districts located in the vicinity of gas-processing works. The ambient air, the blanket of snow, and drinking water were assessed for pollution. The drinking water and ambient air in vicinity of the works were found to be polluted by toxic substances.