RESUMO
Using SVZ (subventricular zone) tissue explants from one-day-old mice, we investigated the activity of new amino aromatic disulfide analogues and polyazamacrocycles on the migration of SVZ cells (neuroblasts). We found that among the tested analogues, non-peptidic disulfide derivative 8 significantly decreases the migration of neuroblasts from SVZ cells, and antagonized the stimulating activity of disulfide cyclic peptide 1. Discovery of compounds 1 and 8 constitutes new chemical tools which could be used to understand the mechanism of neuroblast migration during neurogenesis and eventually to identify specific genes involved in the neurogenesis.
Assuntos
Compostos Aza/farmacologia , Movimento Celular/efeitos dos fármacos , Dissulfetos/farmacologia , Compostos Macrocíclicos/farmacologia , Neurônios/efeitos dos fármacos , Poliaminas/farmacologia , Animais , Compostos Aza/síntese química , Compostos Aza/química , Dissulfetos/síntese química , Dissulfetos/química , Desenho de Fármacos , Ventrículos Laterais/citologia , Ventrículos Laterais/efeitos dos fármacos , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Camundongos , Neurônios/citologia , Peptídeos Cíclicos/química , Poliaminas/síntese química , Poliaminas/químicaRESUMO
A series of twenty six 8-hydroxyquinoline substituted amines, structurally related to compounds 2 and 3, were synthesized to evaluate the effects of structural changes on antitumor activity and understand their mechanism of action. The studies were performed on a wide variety of cancer cell lines within glioma and carcinoma models. The results obtained from chemical models and biological techniques such as microarrays suggest the following hypothesis that a quinone methide intermediate which does not react with DNA but which gives covalent protein thiol adducts. Micro-array analysis showed that the drugs induce the expression of a variety of stress related genes responsible for the cytotoxic and cytostatic effects in carcinoma and glioblastoma cells respectively. The described analogues could represent new promising anti-cancer candidates with specific action mechanisms, targeting accessible thiols from specific proteins and inducing potent anti-cancer effects.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Benzilaminas/química , Benzilaminas/farmacologia , Oxiquinolina/química , Antineoplásicos/metabolismo , Benzoquinonas/química , Benzilaminas/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , DNA/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Concentração Inibidora 50 , Nucleotídeos/metabolismo , Estresse Fisiológico/genética , Relação Estrutura-AtividadeRESUMO
Bis-8-hydroxyquinoline substituted benzylamines have been synthesized and screened for their antitumor activity on KB3 cell line model. Synthesis of this series of new analogues was accomplished using a one pot specific methodology which allows the synthesis of both bis- and mono-8-hydroxyquinoline substituted benzylamines. Among the synthesized compounds two compounds (4a and 5a), respectively, named JLK 1472 and JLK 1486, were particularly potent on KB3 cell line. Their CC(50) values being, respectively, 2.6 and 1.3 nM. Screened on a panel of cell lines showing various phenotype alterations, both compounds were found inactive on some cell lines such as PC3 (prostate cell line) and SF268 (neuroblastoma cell line) while highly active on other different cell lines. Mechanistic studies reveal that these two analogues did not affect tubulin and microtubules neither they exert a proteasomal inhibition effect. In contrast 4a and 5a activate specifically caspase 3/7 and not caspase 8 and 9, suggesting that their biological target should be located upstream from caspase 3/7. Moreover their cytotoxic effect is potentiated by the pro-apoptotic effects of TRAIL.
Assuntos
Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Benzilaminas/síntese química , Antineoplásicos/farmacologia , Benzilaminas/farmacologia , Caspases/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Hidroxiquinolinas , Masculino , Relação Estrutura-Atividade , Ligante Indutor de Apoptose Relacionado a TNFRESUMO
The protease beta-secretase plays a central role in the synthesis of pathogenic amyloid-beta in Alzheimer's disease. Here, we report a new series of analogues based on the phenyl-piperazine scaffold coupled to various heterocyclic moieties, which demonstrate improved inhibitory activities on BACE-1 (FRET assay) compared to already known naphthyl counterparts. The obtained results suggest further structural modifications to access to more potent BACE-1 inhibitors.
Assuntos
Benzopiranos/química , Cumarínicos/química , Endopeptidases/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Piperazinas/farmacologia , Quinolinas/química , Secretases da Proteína Precursora do Amiloide , Piperazinas/químicaRESUMO
Dysfunction of copper metabolism leading to its excess or deficiency results in severe ailments. Recently, neurodegenerative disorders such as Alzheimer's disease have been associated with copper metabolism. Compounds having the ability to reduce copper levels in brain or to affect its distribution could have neuroprotective effects, mainly through a downregulation of the transcription of amyloid peptide precursor (APP). We report here the biological effect of compound 1,1'-xylyl bis-1,4,8,11-tetraaza cyclotetradecane, which specifically affects copper concentration in the brain cortex region. Its copper homeostatic activity is compared with that of clioquinol, a well-known drug, which has been recently reported as an active A beta-peptide clearance drug in vivo for Alzheimer's patients.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Quelantes/farmacologia , Clioquinol/farmacocinética , Cobre/metabolismo , Compostos Heterocíclicos com 1 Anel/química , Compostos Heterocíclicos com 1 Anel/farmacologia , Doença de Alzheimer/líquido cefalorraquidiano , Animais , Quelantes/farmacocinética , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
To find new derivatives that block different virus strains entry in cells bearing specific surface receptors represent an interesting challenge for medicinal chemists. Here, we report the synthesis and the anti-HIV properties of a new series of analogues based on the introduction of quinoline moiety on various polyamine backbones, including polyazamacrocycles. Three compounds 7, 8, and 10 of this series were found active on PBMCs cells infected by HIV-1 LAV or by HIV-1 BaL, in contrast the well-known reference compound 1a (AMD 3100) was found only active on HIV-1 LAV strain.