RESUMEN
Highly potent poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors, including 9-hydroxy-1,2-dihydro-4H-thiopyrano[3,4-c]quinolin-5(6H)-one derivatives with a non-aromatic A-ring, were synthesized. Among the derivatives, 12a showed low nanomolar enzyme and cellular activity (IC(50) = 42 nM, ED(50) = 220 nM) with good water solubility. Further, 12a exhibited microsomal stability in vitro and brain permeability in vivo.
Asunto(s)
Amidas/farmacología , Inhibidores Enzimáticos/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Poli(ADP-Ribosa) Polimerasas/metabolismo , Compuestos Policíclicos/farmacología , Amidas/química , Amidas/farmacocinética , Animales , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/química , Compuestos Policíclicos/química , Compuestos Policíclicos/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
We synthesized a series of delta-lactam-based HDAC inhibitors that were identified with various degrees of anti-inflammatory and cell growth inhibitory activities. Compounds possessing significant HDAC inhibitory activity exhibited both anti-inflammatory and cell growth inhibitory activities as well as significant tumor growth inhibition in the in vivo tumor xenograft experiments. Besides, these compounds demonstrated anti-inflammatory properties in vitro via suppression of the production of the proinflammatory cytokine TNF-alpha and nitric oxide by LPS-stimulated RAW264.7 cells.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Antineoplásicos/síntesis química , Inhibidores de Histona Desacetilasas , Lactamas/síntesis química , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Lactamas/química , Lactamas/farmacología , Lipopolisacáridos/farmacología , Ratones , Modelos Moleculares , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Relación Estructura-Actividad , Trasplante Heterólogo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
PURPOSE: To evaluate simultaneous laser in situ keratomileusis (LASIK) on the stromal bed and the undersurface of the flap in eyes with high myopia and insufficient corneal thickness for conventional LASIK ablation. SETTING: 21 Century Eye Hospital, Seoul Paik Hospital, Inje University, Seoul, Korea. METHODS: Using intraoperative pachymetry, the residual stromal bed thickness was evaluated and simultaneous LASIK was performed on the stromal bed and undersurface of the flap without compromising the posterior 300 mum of the stromal bed. In a prospective series, outcomes in 43 eyes of 27 patients with mean spherical equivalent refraction ranging from -12.5 to -3.75 diopters were analyzed 1, 3, and 6 months after surgery. RESULTS: Postoperative uncorrected visual acuity was 20/30 or better in 35 eyes (81.4%) at 1 month, 36 eyes (83.7%) at 3 months, and 34 eyes (79.1%) at 6 months. During surgery and follow-up, no vision-threatening complications occurred. CONCLUSION: Simultaneous LASIK appears to be a useful surgical aid in LASIK treatment in eyes with high myopia with or without astigmatism when an adequate residual stromal bed does not exist.
Asunto(s)
Córnea/patología , Sustancia Propia/cirugía , Queratomileusis por Láser In Situ , Miopía/fisiopatología , Miopía/cirugía , Colgajos Quirúrgicos , Adulto , Astigmatismo/complicaciones , Astigmatismo/fisiopatología , Humanos , Queratomileusis por Láser In Situ/efectos adversos , Persona de Mediana Edad , Miopía/complicaciones , Miopía/patología , Pronóstico , Estudios Prospectivos , Refracción Ocular , Índice de Severidad de la Enfermedad , Agudeza VisualRESUMEN
delta-Lactam-based hydroxamic acids, inhibitors of histone deacetylase (HDAC), have been synthesized via ring closure metathesis of key diene intermediates followed by conversion to hydroxamic acid analogues. The hydroxamic acids 12a, 12b, and 17c showed potent inhibitory activity in HDAC enzyme assay. The hydroxamic acid 12b exhibited growth inhibitory activity on five human tumor cell lines, showing good sensitivity on the MDA-MB-231 breast tumor cell.