RESUMEN
Inactivation of the NF-κB signaling pathway by inhibition of IKKß is a well-known approach to treat inflammatory diseases such as rheumatoid arthritis and cancer. Thienopyrimidine-based analogues were designed through modification of the known IKKß inhibitor, SPC-839, and then biologically evaluated. The resulting analogues had good inhibitory activity against both nitric oxide and TNF-α, which are well-known inflammatory responses generated by activated NF-κB. However, no inhibitory activity against IKKß was observed with these compounds. The thienopyrimidine-based analogues were subsequently screened for a target kinase, and FLT3, which is a potential target for acute myeloid leukemia (AML), was identified. Thienopyrimidine-based FLT3 inhibitors showed good inhibition profiles against FLT3 under 1µM. Overall, these compounds represent a promising family of inhibitors for future development of a treatment for AML.
Asunto(s)
Quinasa I-kappa B/antagonistas & inhibidores , Pirimidinas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Activación Enzimática/efectos de los fármacos , Humanos , Quinasa I-kappa B/química , Maleimidas/química , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Quinazolinas/química , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
A series of coumarin based TACE inhibitors were designed to bind in S1' pocket of TACE enzyme based on their docking study. Twelve analogues were synthesized and most of compounds were active in vitro TACE enzyme inhibition as well as cellular TNF-α inhibition. Among these, 15l effectively inhibited the production of serum TNF-α by oral administration at a dose of 30 mg/kg. Compound 15l also showed a good oral bioavailability at 42% and effectively inhibited paw edema in rat carrageenan model. Quantitative structure-activity relationship (QSAR) study using genetic function approximation technique (GFA) and docking study were performed to confirm the series of coumarin core TACE inhibitors. QSAR model have been evaluated internally and externally using test set prediction. Through docking study of each molecule, it is validated that the electrostatic descriptors from the QSAR equation could explain the importance of S1' pocket and the TACE inhibitory activity well.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Cumarinas , Relación Estructura-Actividad Cuantitativa , Proteína ADAM17 , Animales , Benzopiranos , Sitios de Unión , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Unión Proteica , Ratas , Electricidad EstáticaRESUMEN
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
A series of coumarin types MMP inhibitors were designed based on gelastatin hydroxamates (1) and evaluated for TACE, cellular TNF-alpha, and NO inhibitory activities. Among them, compounds 9b had potent inhibitory activities in enzymatic and cellular assays and good selectivity to MMP-2 and MMP-9. Further investigation of 9b will be carried out for its efficacy in RA animal model system.
Asunto(s)
Cumarinas , Metaloendopeptidasas/antagonistas & inhibidores , Inhibidores de Proteasas/síntesis química , Proteínas ADAM/antagonistas & inhibidores , Proteína ADAM17 , Ácidos Hidroxámicos , Inhibidores de la Metaloproteinasa de la Matriz , Óxido Nítrico/antagonistas & inhibidores , Inhibidores de Proteasas/farmacología , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
Anti-glycation activity of our anti-oxidant quinone library was measured and several 2,3-dimethoxy-5-methyl-1,4-benzoquinones and 2-methyl-1,4-naphthoquinones were identified as novel inhibitors of glycation, of which 2,3-dimethoxy-5-methyl-1,4-benzoquinones 13b is the most potent glycation inhibitor with around 50 microM of the IC(50) value.
Asunto(s)
Benzoquinonas/síntesis química , Glicosilación/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Naftoquinonas/síntesis química , Animales , Antioxidantes/síntesis química , Antioxidantes/farmacología , Benzoquinonas/farmacología , Productos Finales de Glicación Avanzada/antagonistas & inhibidores , Humanos , Concentración 50 Inhibidora , Naftoquinonas/farmacología , Relación Estructura-ActividadRESUMEN
4-Hydroxyphenylacetic acid amides and 4-hydroxycinnamamides were synthesized and their antioxidant and neuroprotective activities were evaluated. Among the prepared compounds, 8b, and exhibited potent inhibition of lipid peroxidation in rat brain homogenates, and marked DPPH radical scavenging activities. Furthermore, and exhibited neuroprotective action against the oxidative damage induced by the exposure of primary cultured rat cortical cells to H(2)O(2), xanthine/xanthine oxidase, or Fe(2+)/ascorbic acid. Based on these results, we found that was the most potent antioxidant among the compounds tested.