RESUMO
The antioxidant activity and protective effect in the toxicity model of H2O2 were studied for arachidonic (AA-CHOL), docosahexaenoic (DHA-CHOL), linoleic (Ln-CHOL), and oleic (Ol-CHOL) fatty acids, as well as arachidonoyl dicholine (AA-diCHOL) and O-arachidonoyl bistetramethylaminoisopropanol (ABTAP). AA-CHOL, DHA-CHOL and Ln-CHOL provided a 20% increase in cell survival. AA-CHOL, AA-diCHOL, Ol-CHOL, and ABTAP had a radical-scavenging effect in the ABTS test, approximately equal to the activity of a standard radical scavenger Trolox.
Assuntos
Antioxidantes/química , Ácidos Araquidônicos/química , Colina/química , 2-Propanol/química , Ácido Araquidônico/química , Linhagem Celular Tumoral , Cromanos/química , Ácidos Docosa-Hexaenoicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Ácidos Graxos , Radicais Livres/química , Humanos , Peróxido de Hidrogênio/química , Ácido Linoleico/química , Ácido Oleico/químicaRESUMO
The synthesized new binary conjugates of tetrahydro-γ-carbolines, which contained ditriazole spacers of different length, exhibited considerable anticholinesterase and antioxidant activity as well as the potential ability to block the acetylcholinesterase-induced aggregation of ß-amyloid in contrast to the original prototype Dimebon. This makes the compounds promising candidates for further investigation as drugs for the treatment of Alzheimer's disease. Special attention should be given to the conjugate containing the hexamethylene intertriazole spacer, which can be considered as a leader in this series of compounds.
Assuntos
Antioxidantes/química , Carbolinas/química , Inibidores da Colinesterase/química , Doença de Alzheimer/tratamento farmacológico , Animais , Antioxidantes/uso terapêutico , Carbolinas/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Indóis/química , Indóis/uso terapêuticoRESUMO
Using the acylation reaction with tosyl chloride of N-aminopropyl analogues of tacrine and its cyclic homologues with different size of the aliphatic cycle (5-8), we synthesized a number of new derivatives of p-toluenesulfonamide. It is shown that the synthesized hybrid compounds of tacrine and p-toluenesulfonamide are effective inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with the preferential inhibition of BChE. They also displace propidium from the peripheral anionic site of the electric eel AChE (Electrophorus electricus). The characteristics of the efficiency and selectivity of cholinesterase inhibition by the test compounds were confirmed by the results of molecular docking.
Assuntos
Acetilcolinesterase/química , Butirilcolinesterase/química , Inibidores da Colinesterase , Electrophorus , Proteínas de Peixes , Sulfonamidas/química , Tacrina/química , Tolueno/análogos & derivados , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Proteínas de Peixes/antagonistas & inibidores , Proteínas de Peixes/química , Tolueno/químicaRESUMO
Conjugates of tacrine with 1,2,4-thiadiazole derivatives were synthesized for the first time. Their esterase profile and effects on the key NMDA receptor-binding sites as well as antioxidant activity were investigated. The obtained compounds effectively inhibited cholinesterases (with a predominant effect on butyrylcholinesterase), simultaneously blocked two NMDA receptor-binding sites (allosteric and intrachannel sites, and exhibited a high radical-scavenging activity. Our study shows that the obtained compounds are promising to design drugs for the treatment of Alzheimer's disease and other multifactorial neurodegenerative diseases.
Assuntos
Antioxidantes/farmacologia , Inibidores da Colinesterase/química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Tacrina/química , Tiadiazóis/química , Butirilcolinesterase/química , Inibidores da Colinesterase/farmacologia , Humanos , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Tacrina/farmacologia , Tiadiazóis/farmacologiaAssuntos
Hidrolases de Éster Carboxílico/antagonistas & inibidores , Hidrolases de Éster Carboxílico/sangue , Inibidores Enzimáticos/farmacologia , Compostos Organofosforados/farmacologia , Animais , Inibidores Enzimáticos/toxicidade , Camundongos , Compostos Organofosforados/toxicidade , Especificidade por SubstratoAssuntos
Esterases/antagonistas & inibidores , Compostos Organofosforados/química , Compostos Organofosforados/farmacologia , Relação Estrutura-Atividade , Animais , Inibidores da Colinesterase/efeitos adversos , Inibidores da Colinesterase/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lactatos/química , Compostos Organofosforados/efeitos adversos , FosforilaçãoRESUMO
Acetylcholinesterase, butyrylcholinesterase, carboxylesterase, and paraoxonase activities in human, mouse, and rat blood were measured. The proportions of these enzymes activities differed significantly. In humans, the most significant were cholinesterase activities, while in rats and mice the contribution of carboxylesterase activity was the greatest. High arylesterase activity of paraoxonase was observed in all cases. Species-specific differences should be taken into consideration when carrying out preclinical trials on rodents for optimization of the pharmacokinetic characteristics of drugs containing complex ester groups.
Assuntos
Acetilcolinesterase/sangue , Arildialquilfosfatase/sangue , Butirilcolinesterase/sangue , Carboxilesterase/sangue , Adulto , Animais , Animais não Endogâmicos , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Ratos , Ratos Wistar , Especificidade da EspécieRESUMO
Experiments on resting hepatocytes with inactive c-fos gene and active albumin gene. We revealed that DNA of the transcribed gene is less susceptible to the influence of endogenous Ca2+/Mg(2+)-dependent DNases in matrix-associated and highly soluble chromatin fractions. In the fraction of low soluble chromatin active gene was more accessible for DNases. Our results indicate that activity of endogenous DNases can change in the transcribed gene locus.
Assuntos
Cromatina/metabolismo , Desoxirribonucleases/metabolismo , Hepatócitos/metabolismo , Transcrição Gênica , Albuminas/genética , Animais , Regulação da Expressão Gênica , Genes fos , Masculino , Ratos , Ratos WistarRESUMO
Accumulation of c-fos gene locus DNA in the nuclear matrix of hepatocyte nuclei was observed during induction of c-fos with cycloheximide. No enhanced association with the nuclear matrix was detected for inactive immunoglobulin gene locus. The use of endogenous DNAses allows isolation of nuclear matrix preparations enriched with transcribing chromatin.
Assuntos
Cromatina/metabolismo , Genes fos , Matriz Nuclear/metabolismo , Animais , Cromatina/genética , Cicloeximida/metabolismo , Regulação da Expressão Gênica , Hepatócitos/citologia , Hepatócitos/fisiologia , Imunoglobulina G/genética , Masculino , Inibidores da Síntese de Proteínas/metabolismo , Ratos , Ratos WistarRESUMO
Degree of nucleolysis has critical significance for isolation of nuclear matrix (NM) specifically enriched in transcribed DNA sequences as demonstrated at the example of inactive (c-fos, c-myc, and Ck) and active (p53, albumin, and 28S rRNA) genes in resting hepatocytes. Optimal degree of nucleolysis features degradation of loop domains of chromatin with preserved relatively uniform molecular weight distribution of DNA. Deviation from these parameters leads to nonspecific fragmentation of chromatin in various gene loci and isolation of NM samples nonspecifically enriched or depleted of transcribed DNA sequences. Under optimal hydrolytic conditions, the transcribed chromatin is more resistant to endogenous DNase attack, which allows selective conservation of its association with the nuclear matrix.