RESUMO
The methods of synthesis of furano- and pyrrolo[2,3-dlpyrimidine nucleosides as well as structure activity relationship of obtained compounds towards viruses of varicella zoster, hepatitis C, bovine viral diarrhea and some others are reviewed.
Assuntos
Antivirais/síntese química , Hepacivirus/efeitos dos fármacos , Nucleosídeos de Pirimidina/química , Nucleosídeos de Pirimidina/síntese química , Antivirais/química , Antivirais/farmacologia , Linhagem Celular Tumoral , Furanos/síntese química , Furanos/química , Furanos/farmacologia , Hepacivirus/patogenicidade , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Herpes Zoster/tratamento farmacológico , Herpes Zoster/virologia , Herpesvirus Humano 3/efeitos dos fármacos , Herpesvirus Humano 3/patogenicidade , Humanos , Estrutura Molecular , Neoplasias/tratamento farmacológico , Nucleosídeos de Pirimidina/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Inibidores Enzimáticos/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Nucleotídeos de Timina/síntese química , Tuberculose/microbiologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Espectroscopia de Ressonância Magnética , Mycobacterium tuberculosis/enzimologia , Nucleotídeos de Timina/química , Nucleotídeos de Timina/farmacologia , Tuberculose/tratamento farmacológicoRESUMO
The synthetic methods for 4'-C-modified nucleosides as well as structure activity relationship of obtained compounds towards hepatitis C virus are reviewed.
Assuntos
Nucleosídeos de Pirimidina/química , Nucleosídeos de Pirimidina/síntese química , Relação Estrutura-Atividade , RNA Polimerases Dirigidas por DNA/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Humanos , Estrutura Molecular , Nucleosídeos de Pirimidina/farmacologia , RNA Helicases/efeitos dos fármacosRESUMO
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.
Assuntos
Antivirais/síntese química , Furanos/síntese química , Organofosfatos/síntese química , Nucleosídeos de Pirimidina/síntese química , Pirróis/síntese química , Adenosina Trifosfatases/antagonistas & inibidores , Adenosina Trifosfatases/química , Animais , Antivirais/química , Antivirais/farmacologia , Bovinos , Células Cultivadas , Vírus da Diarreia Viral Bovina/efeitos dos fármacos , Vírus da Diarreia Viral Bovina/fisiologia , Furanos/química , Furanos/farmacologia , Hepacivirus/efeitos dos fármacos , Humanos , Organofosfatos/química , Organofosfatos/farmacologia , Nucleosídeos de Pirimidina/química , Nucleosídeos de Pirimidina/farmacologia , Pirróis/química , Pirróis/farmacologia , Replicon , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Replicação Viral/efeitos dos fármacosRESUMO
New 5-azole- and 5-oxime-substituted analogues of 2'-deoxyuridine are synthesized. The analogues with azole ring manifest low toxicities and antiherpetic activities on Vero cell culture, the imidazole derivative being the most active. The inhibitory effects of oximes of 5-formyl-deoxyuridine are comparable with those of the azole-containing nucleoside analogues, although their cytotoxicities are found to be higher; oxime of 5-formyldeoxyuridine is particularly toxic. The nucleoside analogues synthesized exhibit no marked activity on cell cultures infected with various variants of poxvirus. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2005, vol. 31, no. 6; see also http://www.maik.ru.
Assuntos
Antivirais/síntese química , Azóis/síntese química , Desoxiuridina/análogos & derivados , Desoxiuridina/síntese química , Oximas/síntese química , Aciclovir/farmacologia , Animais , Antivirais/farmacologia , Azóis/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Desoxiuridina/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Oximas/farmacologia , Poxviridae/efeitos dos fármacos , Células Vero , Replicação Viral/efeitos dos fármacosRESUMO
We studied the effect of natural antioxidant carnosine on Wistar rats with experimental acoustic trauma of the auditory apparatus. Repeated intraperitoneal injection of carnosine in a dose of 200 mg/kg 12 and 0.5 h before modeling of acute acoustic trauma decreased the severity of degenerative and atrophic changes in the nuclei of hair cells in the cochleae. Carnosine compensated the deficiency of tissue antioxidant systems and suppressed generation of lipid peroxidation products in tissues of the membranous cochlea and auditory cortex of the temporal lobes. Carnosine holds much promise as a nonspecific otoprotector.
Assuntos
Antioxidantes/uso terapêutico , Carnosina/uso terapêutico , Cóclea/patologia , Perda Auditiva Provocada por Ruído/prevenção & controle , Animais , Cóclea/química , Cóclea/efeitos dos fármacos , Células Ciliadas Auditivas/patologia , Perda Auditiva Provocada por Ruído/induzido quimicamente , Perda Auditiva Provocada por Ruído/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Malondialdeído/análise , Ratos , Ratos Wistar , Superóxido Dismutase/análiseRESUMO
Intragastric administration of L-carnosine suspension to Wistar-Kyoto rats 3 days before and after 7-day course of intraperitoneal injections of ototoxic aminoglycoside antibiotic kanamycin compensated expenditures of tissue antioxidant systems and significantly eliminated kanamycin-induced intensification of MDA production in tissues of the membrane part of the cochlea and in the auditory cortex of the temporal lobe. L-NAME (competitive NO synthase inhibitor) also inhibited LPO, increased total antioxidant activity, and decreased ototoxicity of kanamycin, which confirms the contribution of NO into LPO intensification under conditions of aminoglycoside treatment. Inhibition of pathological intensification of LPO processes and increase in total antioxidant activity under conditions of induced acute aminoglycoside ototoxicity characterizes L-carnosine as a highly effective otoprotector.
Assuntos
Antioxidantes/farmacologia , Córtex Auditivo/efeitos dos fármacos , Córtex Auditivo/metabolismo , Carnosina/farmacologia , Cóclea/efeitos dos fármacos , Cóclea/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Animais , Antibacterianos/administração & dosagem , Antibacterianos/toxicidade , Córtex Auditivo/lesões , Cóclea/lesões , Canamicina/administração & dosagem , Canamicina/toxicidade , Masculino , Malondialdeído/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Ratos , Ratos Endogâmicos WKYRESUMO
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.
Assuntos
Antivirais/farmacologia , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 1/efeitos dos fármacos , Organofosfonatos/farmacologia , Tionucleosídeos/fisiologia , Animais , Antivirais/química , Antivirais/toxicidade , Chlorocebus aethiops , Herpes Simples/virologia , Camundongos , Organofosfonatos/química , Organofosfonatos/toxicidade , Relação Estrutura-Atividade , Tionucleosídeos/química , Tionucleosídeos/toxicidade , Testes de Toxicidade Aguda , Células VeroRESUMO
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.
Assuntos
Antivirais/síntese química , Desoxiuridina/análogos & derivados , Desoxiuridina/síntese química , Herpesvirus Humano 1/efeitos dos fármacos , Organofosfonatos/química , Animais , Antivirais/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Desoxiuridina/farmacologia , Estabilidade de Medicamentos , Herpesvirus Humano 1/crescimento & desenvolvimento , Humanos , Células VeroRESUMO
Novel beta-H-phosphono-alpha-phosphonomethyl analogues of nucleoside 5'-diphosphates were synthesized by phosphonylation of 5'-O-phosphonomethylthymidine and 9-[2-phosphonomethyloxy)ethyl]adenine with sodium pyrophosphite. The structures of the resulting individual compounds were confirmed by NMR and UV spectroscopy.
Assuntos
Nucleotídeos/síntese química , Espectroscopia de Ressonância Magnética , Nucleotídeos/química , OrganofosfonatosRESUMO
A new reagent for photoaffinity modification of biopolymers, 5-[E-N-(2-nitro-5-azidobenzoyl)-3-amino-1-propen-1-yl]-2',3'-dideoxyuridine 5'-triphosphate (NAB-ddUTP), was synthesized. Like a similar derivative of 2'-deoxyuridine 5'-triphosphate (NAB-dUTP), it was shown to be able to effectively substitute for dTTP in the synthesis of DNA catalyzed by eukaryotic DNA polymerase beta and to terminate DNA synthesis. A 5'-32P-labeled primer with a photoreactive group at the 3'-terminus was derived from NAB-ddUTP and used for photoaffinity labeling of the human replication protein A (RPA). The covalent attachment of RPA p32 and p70 subunits to the labeled primers was demonstrated. NAB-ddUTP is a promising tool for studying the interaction of proteins of the replicative complex with NA in cellular extracts and living cells during the termination of DNA synthesis.
Assuntos
Proteínas de Ligação a DNA/química , Nucleotídeos de Uracila/química , Didesoxinucleotídeos , Humanos , Marcadores de Fotoafinidade , Proteína de Replicação ARESUMO
Described in the article is one of the forms of optimization of the instructional process in the postgraduation physician training--"business-like games". Highly skilled, competent position of the teacher who conducts a business-like game secures an active participation in learning of students, helps in opening the mind, broadening the outlook on the problem under consideration, gives much incentive to further independent work on the discussed issues.
Assuntos
Educação Médica Continuada/métodos , Jogos Experimentais , Ensino/métodos , Diagnóstico Diferencial , Humanos , Resolução de Problemas , UcrâniaAssuntos
DNA Polimerase Dirigida por DNA/metabolismo , Fosfatos de Dinucleosídeos/genética , Fosfatos de Dinucleosídeos/metabolismo , Sequência de Bases , Fosfatos de Dinucleosídeos/química , Escherichia coli , Humanos , Dados de Sequência Molecular , Fosforilação , Análise de Sequência , Especificidade por SubstratoRESUMO
The development of effective methods for preventing and correcting myopia in pilots is one of the most important problems of aeronautic ophthalmology. The majority of Russian and foreign aeronautic ophthalmologists agree that contact correction is the principal method for repair of occupational vision of myopic pilots. Experiments with soft contact lenses with 38 and 70% humor content were carried out. The methodology was based on comprehensive examinations of the vision status and status of the organ of vision under common conditions on the Earth and during simulation of unfavorable flight factors. The results indicate that contact lenses are a safe means for correcting myopia in pilots. This is confirmed by the absence of unfavorable changes in the main visual functions and in the status of the anterior segment of the eye, by a constant level of visual working capacity, and by the absence of negative subjective sensations.
Assuntos
Acomodação Ocular/fisiologia , Lentes de Contato Hidrofílicas , Miopia/terapia , Adolescente , Adulto , Medicina Aeroespacial , Humanos , Masculino , Miopia/fisiopatologia , Oftalmologia/métodos , Segurança , Resultado do Tratamento , Acuidade VisualRESUMO
Opening of ATP-sensitive K+ (KATP) channels by the uncoupler of oxidative phosphorylation, 2,4 dinitrophenol (DNP), has been assumed to be secondary to metabolic inhibition and reduced intracellular ATP levels. Herein, we present data which show that DNP (200 microM) can induce opening of cardiac KATP channels, under whole-cell and inside-out conditions, despite millimolar concentrations of ATP (1-2. 5 mm). DNP-induced currents had a single channel conductance (71 pS), inward rectification, reversal potential, and intraburst kinetic properties (open time constant, tauopen: 4.8 msec; fast closed time constant, tauclosed(f): 0.33 msec) characteristic of KATP channels suggesting that DNP did not affect the pore region of the channel, but may have altered the functional coupling of the ATP-dependent channel gating. A DNP analogue, with the pH-titrable hydroxyl replaced by a methyl group, could not open KATP channels. The pH-dependence of the effect of DNP on channel opening under whole-cell, cell-attached, and inside-out conditions suggested that transfer of protonated DNP across the sarcolemma is essential for activation of KATP channels in the presence of ATP. We conclude that the use of DNP for metabolic stress-induced KATP channel opening should be reevaluated.
Assuntos
Trifosfato de Adenosina/metabolismo , Dinitrofenóis/farmacologia , Coração/fisiologia , Ativação do Canal Iônico/fisiologia , Miocárdio/metabolismo , Canais de Potássio/metabolismo , Sarcolema/metabolismo , Desacopladores/farmacologia , Animais , Cobaias , Coração/efeitos dos fármacos , Técnicas In Vitro , Ativação do Canal Iônico/efeitos dos fármacos , Miocárdio/citologia , Canais de Potássio/efeitos dos fármacos , Sarcolema/efeitos dos fármacosRESUMO
This study used the colorimetric MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide)] assay to assess cell viability in isolated quiescent adult guinea-pig ventricular myocytes exposed to different insults or cardioprotective conditions, including adenosine and hyperkalemic-cardioplegia. Optical density (OD), reflecting intracellular reduction of MTT into formazan pigment formation, was a function of the number of viable cells (coefficient of linear correlation approximately 0.99), with MTT reduction preferentially carried out by rod-shaped cardiomyocytes (absorbance at 1.009 +/- 0.013 and 0.006 +/- 0.001 OD units for populations containing 50 and 0% of rod-shaped cells). Following prolonged mechanical (pressure of 1 lb/min for 40 min), chemical (10% DMSO or ethanol) or hypoxic injury (N2-saturated solution), the MTT reductase activity reflected reduction in the number of viable cells by 87%, >50%, and 77%, respectively. In cardiomyocytes exposed to a 40 min hypoxia (with CO2), the MTT reductase activity was 0.056 +/- 0.009 in the absence, and 0.074 +/- 0.008 OD units in the presence of adenosine (1 mM), i.e. adenosine reduced the number of non-viable cells. Also, the MTT assay revealed that the effect of potassium-containing solutions (16 and 32 mM K+) on cellular viability may depend on the extent of insult imposed on cardiomyocytes; i.e. a approximately 24% and 49% increase under mild hypoxia (0.03% CO2), or an 18% decrease in cell viability under severe hypoxia (N2) in pre-injured cells. Thus, the MTT assay used to assess viability of isolated adult cardiomyocytes revealed a direct cytoprotective effect of adenosine and hyperkalemic-cardioplegia by promoting cell survival under certain conditions in vitro.
Assuntos
Adenosina/farmacologia , Ventrículos do Coração/citologia , Potássio/farmacologia , Espectrofotometria/métodos , Sais de Tetrazólio/metabolismo , Fatores Etários , Animais , Soluções Cardioplégicas/farmacologia , Adesão Celular , Morte Celular/efeitos dos fármacos , Dimetil Sulfóxido/toxicidade , Cobaias , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/lesões , Hipóxia/induzido quimicamente , Hipóxia/metabolismo , Nitrogênio/toxicidade , Oxirredução , Fenótipo , Estresse MecânicoRESUMO
The efficacy with which sulfonylurea drugs inhibit cardiac ATP-sensitive K+ (KATP) channels is reduced during metabolic compromise and cellular contracture. Disruption of the actin microfilament network, which occurs under similar conditions, reduces the sensitivity of the channel toward intracellular ATP. To investigate whether a disrupter of actin microfilaments could also affect the responsiveness of the KATP channel to sulfonylurea drugs, single-channel currents were measured in the inside-out configuration of excised patches from guinea pig ventricular myocytes. Treatment of the internal side of patches with deoxyribonuclease (DNase) I (100 micrograms/ml), which forms complexes with G actin and prevents actin filament formation, antagonized sulfonylurea-induced inhibition of KATP channels that was coupled with a loss of sensitivity to ATP. The apparent dissociation constant and Hill coefficient for the inhibitory effect of glyburide, a prototype sulfonylurea, on KATP-channel opening were, respectively, 0.13 microM and 0.95 before and 2.7 microM and 0.98 after DNase treatment. DNase did not alter intraburst kinetic properties of the channel. When DNase was denatured or coincubated with purified actin (200 micrograms/ml), it no longer decreased glyburide-induced channel inhibition. This suggests that sulfonylurea-inhibitory gating of cardiac KATP channels may also be regulated through a mechanism involving subsarcolemmal actin microfilament networks.
Assuntos
Citoesqueleto de Actina/efeitos dos fármacos , Actinas/efeitos dos fármacos , Trifosfato de Adenosina/farmacologia , Desoxirribonuclease I/farmacologia , Glibureto/farmacologia , Ativação do Canal Iônico/efeitos dos fármacos , Miocárdio/metabolismo , Canais de Potássio/efeitos dos fármacos , Compostos de Sulfonilureia/farmacologia , Actinas/farmacologia , Animais , Relação Dose-Resposta a Droga , Cobaias , Temperatura Alta , Cinética , Concentração Osmolar , Bloqueadores dos Canais de Potássio , Canais de Potássio/metabolismoRESUMO
Replacement of the 10-methoxy group of colchicine by amino and amino acid substituents sharply decreased its toxicity and only slightly decreased its tubulin-binding activity, and thus, gave rise to a number of weakly toxic colchicine analogs. In particular, highly active 10-(N-glycino)-10-demethoxycolchicine and 10-[N-(beta-alanino)]-10-demethoxycolchicine were prepared.
Assuntos
Colchicina/química , Aminas/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Colchicina/síntese química , Colchicina/toxicidade , Camundongos , Conformação Molecular , Células Tumorais CultivadasRESUMO
This study was aimed at comprehensive examination of the visual status of residents of the Northern regions within the frames of investigations on the problem of vision deterioration in the residents of the North. The study covered seven regions of the Koryak Autonomous Territory. A total of 1067 patients were examined, 30% of these were children aged mostly from 6 to 12. About half the examinees were indigenous population of the North. On the whole, the results coincide with previous findings. At the same time, the incidence of myopia is somewhat higher than 10-15 years before. This increase is caused by two principal groups of factors: social and visual. The authors emphasize that the level of ophthalmologic care of the population in the Northern regions is to be improved and measures preventing diseases of the organ of vision be strictly adhered to.