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1.
Mol Biol (Mosk) ; 57(4): 717-725, 2023.
Artigo em Russo | MEDLINE | ID: mdl-37528794

RESUMO

Enzymatic methyltransferase reactions are of crucial importance for cell metabolism. S-Adenosyl-L-methionine (AdoMet) is a main donor of the methyl group. DNA, RNA, proteins, and low-molecular-weight compounds are substrates of methyltransferases. In mammals, DNA methyltransferase Dnmt3a de novo methylates the C5 position of cytosine residues in CpG sequences in DNA. The methylation pattern is one of the factors that determine the epigenetic regulation of gene expression. Here, interactions with the catalytic domain of Dnmt3a was for the first time studied for phosphonous and phosphonic analogs of AdoMet and S-adenosyl-L-homocysteine (AdoHcy), in which the carboxyl group was substituted for respective phosphorus-containing group. These AdoMet analogs were shown to be substrates of Dnmt3a, and the methylation efficiency was only halved as compared with that of natural AdoMet. Both phosphorus-containing analogs of AdoHcy, which is a natural methyltransferase inhibitor, showed similar inhibitory activities toward Dnmt3a and were approximately four times less active than AdoHcy. The finding that the phosphonous and phosphonic analogs are similar in activity was quite unexpected because the geometry and charge of their phosphorus-containing groups differ substantially. The phosphorus-containing analogs of AdoMet and AdoHcy are discussed as promising tools for investigation of methyltransferases.


Assuntos
S-Adenosil-Homocisteína , S-Adenosilmetionina , Animais , S-Adenosilmetionina/metabolismo , S-Adenosil-Homocisteína/metabolismo , S-Adenosil-Homocisteína/farmacologia , Epigênese Genética , Metionina/metabolismo , Metiltransferases/metabolismo , DNA/metabolismo , Mamíferos
2.
Acta Naturae ; 12(3): 140-144, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33173604

RESUMO

Homeostasis of the biogenic polyamines spermine (Spm) and spermidine (Spd), present in µM-mM concentrations in all eukaryotic cells, is precisely regulated by coordinated activities of the enzymes of polyamine synthesis, degradation, and transport, in order to sustain normal cell growth and viability. Spermine oxidase (SMOX) is the key and most recently discovered enzyme of polyamine metabolism that plays an essential role in regulating polyamine homeostasis by catalyzing the back-conversion of Spm to Spd. The development of many types of epithelial cancer is associated with inflammation, and disease-related inflammatory stimuli induce SMOX. MDL72527 is widely used in vitro and in vivo as an irreversible inhibitor of SMOX, but it is also potent towards N1-acetylpolyamine oxidase. Although SMOX has high substrate specificity, Spm analogues have not been systematically studied as enzyme inhibitors. Here we demonstrate that 1,12-diamino-2,11-bis(methylidene)-4,9-diazadodecane (2,11-Met2-Spm) has, under standard assay conditions, an IC50 value of 169 µM towards SMOX and is an interesting instrument and lead compound for studying polyamine catabolism.

3.
Bioorg Khim ; 41(5): 612-8, 2015.
Artigo em Russo | MEDLINE | ID: mdl-26762100

RESUMO

Earlier unknown enantiomerically pure (R)- and (S)-1,8-diamino-3-methyl-4-azaoctane's (3-MeSpd's) were synthesized with high overall yields and optical purity starting from commercially available R- and S-isomers of N-Boc-2-aminopropanol-1. Application of R- and S-isomers of 3-MeSpd for the investigation of the stereospecificity of spermidine transporter and peculiarities of deoxyhypusine synthase reaction are discussed.


Assuntos
Espermidina/análogos & derivados , Espermidina/síntese química , Catálise , Linhagem Celular Tumoral , Humanos , Estrutura Molecular , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/química , Espermidina/química , Espermidina/metabolismo , Estereoisomerismo
4.
Amino Acids ; 46(3): 621-31, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24129980

RESUMO

Histamine plays highlighted roles in the development of many common, emergent and rare diseases. In mammals, histamine is formed by decarboxylation of L-histidine, which is catalyzed by pyridoxal-5'-phosphate (PLP) dependent histidine decarboxylase (HDC, EC 4.1.1.22). The limited availability and stability of the protein have delayed the characterization of its structure-function relationships. Our previous knowledge on mammalian HDC, derived from both in silico and experimental approaches, indicates that an effective competitive inhibitor should be capable to form an "external aldimine-like structure" and have an imidazole group, or its proper mimetic, which provides additional affinity of PLP-inhibitor adduct to the HDC active center. This is confirmed using HEK-293 cells transfected to express human HDC and the aminooxy analog of histidine, 4(5)-aminooxymethylimidazole (O-IMHA, IC50 ≈ 2 × 10(-7) M) capable to form a PLP-inhibitor complex (oxime) in the enzyme active center. Taking advantage of the availability of the human HDC X-ray structure, we have also determined the potential interactions that could stabilize this oxime in the active site of mammalian HDC.


Assuntos
Inibidores Enzimáticos/farmacologia , Histidina Descarboxilase/antagonistas & inibidores , Hidroxilaminas/farmacologia , Imidazóis/farmacologia , Inibidores Enzimáticos/química , Histidina Descarboxilase/metabolismo , Humanos , Hidroxilaminas/química , Imidazóis/química , Simulação de Dinâmica Molecular , Estrutura Molecular , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
5.
Biochemistry (Mosc) ; 78(13): 1431-46, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24490733

RESUMO

The biogenic polyamines spermine, spermidine, and their precursor putrescine are present in micro-to-millimolar concentrations in all cell types and are vitally important for their normal growth. High intracellular content of spermine and spermidine determines the multiplicity of the cellular functions of the polyamines. Many of these functions are not well characterized at the molecular level, ensuring the ongoing development of this field of biochemistry. Tumor cells have elevated polyamine level if compared with normal cells, and this greatly stimulates the search for new opportunities to deplete the intracellular pool of spermine and spermidine resulting in decrease in cell growth and even cell death. O-Substituted hydroxylamines occupy their own place among chemical regulators of the activity of the enzymes of polyamine metabolism. Varying the structure of the alkyl substituent made it possible to obtain within one class of chemical compounds highly effective inhibitors and regulators of the activity of all the enzymes of putrescine, spermine and spermidine metabolism (with the exception of FAD-dependent spermine oxidase and acetylpolyamine oxidase), effectors of the polyamine transport system, and even actively transported in cells "proinhibitor" of ornithine decarboxylase. Some principles for the design of specific inhibitors of these enzymes as well as the peculiarities of cellular effects of corresponding O-substituted hydroxylamines are discussed.


Assuntos
Hidroxilamina/metabolismo , Espermidina/biossíntese , Espermina/biossíntese , Animais , Humanos , Ornitina Descarboxilase/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/metabolismo , Poliamina Oxidase
6.
Biochemistry (Mosc) ; 77(10): 1172-80, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23157297

RESUMO

Influence of the biogenic polyamines spermine, spermidine, and putrescine as well as their derivatives on the replication enzymes of hepatitis C virus (HCV) was investigated. It was found that spermine and spermidine activate HCV RNA-dependent RNA polymerase (NS5B protein). This effect was not caused by the stabilization of the enzyme or by competition with template-primer complex, but rather it was due to achievement of true maximum velocity V(max). Natural polyamines and their derivatives effectively inhibited the helicase reaction catalyzed by another enzyme of HCV replication - helicase/NTPase (NS3 protein). However, these compounds affected neither the NTPase reaction nor its activation by polynucleotides. Activation of the HCV RNA polymerase and inhibition of the viral helicase were shown at physiological concentrations of the polyamines. These data suggest that biogenic polyamines may cause differently directed effects on the replication of the HCV genome in an infected cell.


Assuntos
Hepacivirus/enzimologia , Putrescina/farmacologia , RNA Helicases/antagonistas & inibidores , RNA Helicases/metabolismo , RNA Polimerase Dependente de RNA/metabolismo , Espermidina/farmacologia , Espermina/farmacologia , Ativação Enzimática/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Humanos , Putrescina/análogos & derivados , RNA Polimerase Dependente de RNA/química , Espermidina/análogos & derivados , Espermina/análogos & derivados , Proteínas não Estruturais Virais/efeitos dos fármacos
7.
Acta Naturae ; 3(4): 94-9, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22649708

RESUMO

Fluoroquinolones are an important class of modern and efficient antibacterial drugs with a broad spectrum of activity. Levofloxacin (the optically active form of ofloxacin) is one of the most promising fluoroquinolone drugs, and its antibacterial activity is substantially higher than the activity of other drugs of the fluoroquinolone family. Earlier, in the Postovsky Institute of Organic Synthesis, UB RAS, an original method of levofloxacin synthesis was developed, and now the pilot batch of the drug is being prepared. Bacterial DNA gyrase is a specific target of fluoroquinolones; hence, the study of the enzyme-drug interaction is of theoretical and practical importance. Moreover, the parameters of DNA gyrase inhibition may serve as a criterion for drug quality. Here, we present the results of studying the interaction of DNA gyrase with a number of fluoroquinolones and their analogs: intermediates and semi-products of the levofloxacin synthesis, and also samples from the pilot batches of this drug. The importance of two structural elements of the levofloxacin molecule for the efficiency of the inhibition is revealed. The data obtained may be useful for the design of new drugs derived from levofloxacin.

9.
Pancreatology ; 10(2-3): 208-21, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20453551

RESUMO

BACKGROUND/AIMS: Polyamines are ubiquitous organic cations essential for cellular proliferation and tissue integrity. We have previously shown that pancreatic polyamine depletion in rats overexpressing the catabolic enzyme, spermidine/spermine N(1)-acetyltransferase (SSAT), results in the development of severe acute pancreatitis, and that therapeutic administration of metabolically stable alpha-methylated polyamine analogs protects the animals from pancreatitis-associated mortality. Our aim was to elucidate the therapeutic mechanism(s) of alpha-methylspermidine (MeSpd). METHODS: The effect of MeSpd on hemostasis and the extent of organ failure were studied in SSAT transgenic rats with either induced pancreatitis or lipopolysaccharide (LPS)-induced coagulopathy. The effect of polyamines on fibrinolysis and coagulation was also studied in vitro. RESULTS: Pancreatitis caused a rapid development of intravascular coagulopathy, as assessed by prolonged coagulation times, decreased plasma fibrinogen level and antithrombin activity, enhanced fibrinolysis, reduced platelet count and presence of schistocytes. Therapeutic administration of MeSpd restored these parameters to almost control levels within 24 h. In vitro, polyamines dose-dependently inhibited fibrinolysis and intrinsic coagulation pathway. In LPS-induced coagulopathy, SSAT transgenic rats were more sensitive to the drug than their syngeneic littermates, and MeSpd-ameliorated LPS-induced coagulation disorders. CONCLUSION: Pancreatitis-associated mortality in SSAT rats is due to coagulopathy that is alleviated by treatment with MeSpd.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Hemostasia/efeitos dos fármacos , Pancreatite/tratamento farmacológico , Espermidina/análogos & derivados , Acetiltransferases/genética , Animais , Transtornos da Coagulação Sanguínea/metabolismo , Modelos Animais de Doenças , Fibrinólise/efeitos dos fármacos , Pancreatite/induzido quimicamente , Pancreatite/patologia , Poliaminas/metabolismo , Ratos , Ratos Transgênicos , Espermidina/uso terapêutico
10.
Mol Biol (Mosk) ; 43(2): 274-85, 2009.
Artigo em Russo | MEDLINE | ID: mdl-19425496

RESUMO

Biogenic amines spermine and spermidine are essential factors of cellular growth. Polyamine analogues are widely used to investigate and to regulate the enzymes of polyamine metabolism and functions of spermine and spermidine in vitro and in vivo. Recently, it was demonstrated that alpha-methylated derivatives of spermine and spermidine are capable to fulfill key cellular functions of polyamines, moreover in some cases of (R)- and (S)-isomers are actually different. Using these alpha-methylated spermine and spermidine analogues it turned possible to prevent the development of acute pancreatitis of SSAT-transgenic rats and to demostrate for the first time that polyamine oxidase, spermine oxidase and deoxyhypusine synthase have dormant stereospecificity. An original approach to regulate the stereospecificity of polyamine oxidase was suggested. It was also demonstrated that the depletion of the intracellular polyamine pool has both hypusine-related consequences and also the consequences unrelated to the posttranslational modification of eukaryotic initiation translation factor eIF5A. Possible applications of a new family of C-methylated polyamine analogues for the investigation and regulation of polyamine metabolism in vitro and in vivo are discussed.


Assuntos
Enzimas/metabolismo , Espermidina/análogos & derivados , Espermidina/metabolismo , Espermina/análogos & derivados , Espermina/metabolismo , Animais , Humanos , Metilação , Fatores de Iniciação de Peptídeos/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Proteínas de Ligação a RNA/metabolismo , Ratos , Ratos Transgênicos , Espermidina/química , Espermina/química , Fator de Iniciação de Tradução Eucariótico 5A
11.
Amino Acids ; 33(2): 323-30, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17410333

RESUMO

The markers of oxidative stress and inflammation were studied in acute pancreatitis in transgenic rats exhibiting activated polyamine catabolism. In addition, the effect of bismethylspermine (Me(2)Spm) pretreatment, preventing pancreatitis in this model, on these mediators was investigated. Lipid peroxidation was increased at 6 and 24 h after induction of pancreatitis. These changes as well as the markedly decreased superoxide dismutase activity at 24 h were abolished by Me(2)Spm pretreatment. Glutathione level and catalase activity changed transiently, and the effect of Me(2)Spm was clear at 24 h. Serum inflammatory cytokine levels increased already at 4 h whereas NF-kappaB was distinctly activated only at 24 h. Me(2)Spm prevented the increase in TNF-alpha and IL-6 while it had no effect on NF-kappaB activation. These results show that typical inflammatory and, to a lesser degree, some oxidative stress mediators are involved and beneficially affected by the disease-ameliorating polyamine analogue in our pancreatitis model.


Assuntos
Estresse Oxidativo/fisiologia , Pancreatite/etiologia , Poliaminas/metabolismo , Acetiltransferases/metabolismo , Doença Aguda , Animais , Animais Geneticamente Modificados , Inflamação/complicações , Interleucina-10/sangue , Interleucina-1beta/sangue , Interleucina-6/sangue , NF-kappa B/metabolismo , Óxido Nítrico/sangue , Pancreatite/patologia , Ratos , Espermina/análogos & derivados , Espermina/farmacologia , Fator de Necrose Tumoral alfa/sangue , Zinco
12.
Biochem Soc Trans ; 35(Pt 2): 369-73, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17371280

RESUMO

The design and synthesis of SpmTrien (1,12-diamino-3,6,9-triazadodecane), an isosteric and charge-deficient analogue of spermine with excellent chelating properties towards Cu(2+) ions, as well as novel N(1)- and N(12)-Ac-SpmTriens and bis-Et-SpmTrien (N(1),N(12)-diethyl-1,12-diamino-3,6,9-triazadodecane) are described. Possible applications of SpmTrien and its derivatives to the investigation of the enzymes of polyamine metabolism and spermine cellular functions, including interaction with DNA, are discussed.


Assuntos
Espermina/análogos & derivados , Espermina/síntese química , Aminas/análise , Quelantes/síntese química , Quelantes/farmacologia , Desenho de Fármacos , Concentração de Íons de Hidrogênio , Modelos Moleculares , Espermidina/análogos & derivados , Espermidina/síntese química , Espermidina/farmacologia , Espermina/farmacologia
13.
Biochem Soc Trans ; 35(Pt 2): 401-4, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17371286

RESUMO

The charge of the agmatine analogues AO-Agm [N-(3-aminooxypropyl)guanidine], GAPA [N-(3-aminopropoxy)guanidine] and NGPG [N-(3-guanidinopropoxy)guanidine] is deficient as compared with that of agmatine and they are thus able to inhibit agmatine transport in liver mitochondria. The presence of the guanidine group is essential for an optimal effect, since AO-Agm and NGPG display competitive inhibition, whereas that of GAPA is non-competitive. NGPG is the most effective inhibitor (K(i)=0.86 mM). The sequence in the inhibitory efficacy is not directly dependent on the degree of protonation of the molecules; in fact NGPG has almost the same charge as GAPA. When the importance of the guanidine group for agmatine uptake is taken into account, this observation suggests that the agmatine transporter is a single-binding, centre-gated pore rather than a channel.


Assuntos
Agmatina/metabolismo , Agmatina/farmacologia , Mitocôndrias Hepáticas/metabolismo , Agmatina/análogos & derivados , Animais , Arginina/metabolismo , Transporte Biológico/efeitos dos fármacos , Cinética , Lisina/metabolismo , Mitocôndrias Hepáticas/efeitos dos fármacos , Ornitina/metabolismo , Ratos
14.
Bioorg Khim ; 32(6): 643-50, 2006.
Artigo em Russo | MEDLINE | ID: mdl-17180915

RESUMO

Convenient methods of synthesis of 1-aminooxy-3,8-diaza-11-aminoundecane, its earlier unknown N1-and N1 -acetyl derivatives, and also 1,10-bis(aminooxy)-3,8-diazadecane are suggested. It is shown a possibility to selectively delete the acid-labile ethoxyethylidene protection of aminooxy group by hydrosulfates in the presence of N-tert-butyloxycarbonyl group.


Assuntos
Espermina/análogos & derivados , Espermina/síntese química
15.
Bull Exp Biol Med ; 141(6): 760-2, 2006 Jun.
Artigo em Inglês, Russo | MEDLINE | ID: mdl-17364069

RESUMO

The rigidity of neutrophilic granulocyte membrane was determined: 2.1+/-0.7 kPa. Scanning in the contact mode did not modify cell morphology, while spectroscopy caused nonspecific swelling reaction and a 3-fold increase in cell volume. Spectroscopy had no effect on rigidity of neutrophilic granulocyte membrane.


Assuntos
Membrana Celular/ultraestrutura , Microscopia de Varredura por Sonda/métodos , Neutrófilos/citologia , Elasticidade , Humanos , Análise Espectral
16.
Bioorg Khim ; 31(6): 645-50, 2005.
Artigo em Russo | MEDLINE | ID: mdl-16363138

RESUMO

N,N'-Di-Boc-N"-triflylguanidine was demonstrated to be an efficient guanidinylation reagent for O-substituted hydroxylamines. N-(3-Aminooxypropyl)- and N-(3-aminopropoxy)guanidines, previously unknown isosteric and charge-deficient agmatine analogues, have been synthesized. The possibilities of using these compounds in studying polyamine metabolism are discussed. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2005, vol. 31, no. 6; see also http://www.maik.ru.


Assuntos
Agmatina/análogos & derivados , Agmatina/síntese química , Agmatina/química
17.
Bioorg Khim ; 31(3): 303-11, 2005.
Artigo em Russo | MEDLINE | ID: mdl-16004389

RESUMO

1,12-Diamino-3,6,9-triazadodecane, a new isosteric and charge-deficient analogue of spermine, is synthesized. Unlike spermine, the new analogue is an excellent chelator of Cu2+ ions. Possible applications of this compound for studying enzymes of polyamine metabolism and cellular functions of spermine are discussed. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2005, vol. 31, no. 3; see also http://www.maik.ru.


Assuntos
Quelantes/química , Cobre/química , Espermina/análogos & derivados , Espermina/química , Quelantes/síntese química , Espermina/síntese química
18.
Bioorg Khim ; 31(2): 206-12, 2005.
Artigo em Russo | MEDLINE | ID: mdl-15889796

RESUMO

A new isosteric charge-deficient spermine analogue, 1,12-diamino-4,9-diaza-5-oxadodecan, and O-(7-amino-4-azaheptyl)oxime of 3-aminopropanal, a stable analogue of the Schiff base intermediate in the enzymatic oxidation of spermine, were synthesized. The possible use of these compounds for the inhibition of spermine oxidase is discussed.


Assuntos
Bases de Schiff/síntese química , Espermina/análogos & derivados , Espermina/síntese química , Espectroscopia de Ressonância Magnética , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/antagonistas & inibidores , Bases de Schiff/química , Espermina/química , Poliamina Oxidase
19.
Bioorg Khim ; 31(2): 200-5, 2005.
Artigo em Russo | MEDLINE | ID: mdl-15889795

RESUMO

alpha-Methylspermine and alpha,alpha'-dimethylspermine were synthesized in high overall yields starting from N-(benzyloxycarbonyl)-3-aminobutanol in order to study polyamine biochemistry in vitro and in vivo.


Assuntos
Espermina/análogos & derivados , Espermina/síntese química , Espectroscopia de Ressonância Magnética/métodos , Espermina/química , Estereoisomerismo
20.
Bioorg Khim ; 30(4): 441-5, 2004.
Artigo em Russo | MEDLINE | ID: mdl-15469020

RESUMO

A five-step synthesis of alpha-methylspermidine (1,8-diamino-5-azanonane), the first polyamine analogue preventing pathological consequences of spermidine depletion in transgenic rats overproducing spermine/spermidine N'-acetyltransferase, from ethyl 3-aminobutyrate was achieved in a high overall yield.


Assuntos
Espermidina/análogos & derivados , Espermidina/síntese química , Animais , Animais Geneticamente Modificados , Espectroscopia de Ressonância Magnética/métodos , Ratos , Espermidina/química
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