RESUMEN
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.
Asunto(s)
Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Bencilaminas/síntesis química , Antineoplásicos/farmacología , Bencilaminas/farmacología , Caspasas/efectos de los fármacos , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Hidroxiquinolinas , Masculino , Relación Estructura-Actividad , Ligando Inductor de Apoptosis Relacionado con TNFRESUMEN
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.
Asunto(s)
Compuestos Aza/farmacología , Movimiento Celular/efectos de los fármacos , Disulfuros/farmacología , Compuestos Macrocíclicos/farmacología , Neuronas/efectos de los fármacos , Poliaminas/farmacología , Animales , Compuestos Aza/síntesis química , Compuestos Aza/química , Disulfuros/síntesis química , Disulfuros/química , Diseño de Fármacos , Ventrículos Laterales/citología , Ventrículos Laterales/efectos de los fármacos , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/química , Ratones , Neuronas/citología , Péptidos Cíclicos/química , Poliaminas/síntesis química , Poliaminas/químicaRESUMEN
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.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , VIH-1/efectos de los fármacos , Hidroxiquinolinas/química , Poliaminas/química , Poliaminas/farmacología , Fármacos Anti-VIH/química , Estructura Molecular , Poliaminas/síntesis química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Quelantes/farmacología , Clioquinol/farmacocinética , Cobre/metabolismo , Compuestos Heterocíclicos con 1 Anillo/química , Compuestos Heterocíclicos con 1 Anillo/farmacología , Enfermedad de Alzheimer/líquido cefalorraquídeo , Animales , Quelantes/farmacocinética , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
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.