RESUMEN
2',5'-Oligoadenylate synthetase (OAS) enzymes and RNase-L constitute a major effector arm of interferon (IFN)-mediated antiviral defense. OAS produces a unique oligonucleotide second messenger, 2',5'-oligoadenylate (2-5A), that binds and activates RNase-L. This pathway is down-regulated by virus- and host-encoded enzymes that degrade 2-5A. Phosphodiesterase 12 (PDE12) was the first cellular 2-5A- degrading enzyme to be purified and described at a molecular level. Inhibition of PDE12 may up-regulate the OAS/RNase-L pathway in response to viral infection resulting in increased resistance to a variety of viral pathogens. We generated a PDE12-null cell line, HeLaΔPDE12, using transcription activator-like effector nuclease-mediated gene inactivation. This cell line has increased 2-5A levels in response to IFN and poly(I-C), a double-stranded RNA mimic compared with the parental cell line. Moreover, HeLaΔPDE12 cells were resistant to viral pathogens, including encephalomyocarditis virus, human rhinovirus, and respiratory syncytial virus. Based on these results, we used DNA-encoded chemical library screening to identify starting points for inhibitor lead optimization. Compounds derived from this effort raise 2-5A levels and exhibit antiviral activity comparable with the effects observed with PDE12 gene inactivation. The crystal structure of PDE12 complexed with an inhibitor was solved providing insights into the structure-activity relationships of inhibitor potency and selectivity.
Asunto(s)
2',5'-Oligoadenilato Sintetasa/inmunología , Antivirales/farmacología , Endorribonucleasas/inmunología , Exorribonucleasas/química , Inmunidad Innata , Bibliotecas de Moléculas Pequeñas/farmacología , 2',5'-Oligoadenilato Sintetasa/genética , Nucleótidos de Adenina/inmunología , Nucleótidos de Adenina/metabolismo , Antivirales/síntesis química , Cristalografía por Rayos X , Virus de la Encefalomiocarditis/genética , Virus de la Encefalomiocarditis/metabolismo , Endorribonucleasas/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Exorribonucleasas/antagonistas & inhibidores , Exorribonucleasas/genética , Exorribonucleasas/inmunología , Regulación de la Expresión Génica , Técnicas de Inactivación de Genes , Células HeLa , Humanos , Interferón-alfa/farmacología , Modelos Moleculares , Oligorribonucleótidos/inmunología , Oligorribonucleótidos/metabolismo , Poli I-C/farmacología , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Virus Sincitiales Respiratorios/genética , Virus Sincitiales Respiratorios/metabolismo , Rhinovirus/genética , Rhinovirus/metabolismo , Transducción de Señal , Bibliotecas de Moléculas Pequeñas/síntesis química , Relación Estructura-ActividadRESUMEN
Inhibition of the signaling pathways of signal transducer and activator of transcription 3 (STAT 3) has shown to be a promising strategy to combat cancer. In this paper we report the design, synthesis and evaluation of a novel class of small molecule inhibitors, that is, XZH-5 and its analogues, as promising leads for further development of STAT3 inhibitors. Preliminary SARs was established for XZH-5 and its derivatives; and the binding modes were predicted by molecular docking. Lead compounds with IC50 as low as 6.5µM in breast cancer cell lines and 7.6µM in pancreatic cancer cell lines were identified.
Asunto(s)
Diseño de Fármacos , Histidina/análogos & derivados , Compuestos de Fenilurea/síntesis química , Compuestos de Fenilurea/farmacología , Factor de Transcripción STAT3/antagonistas & inhibidores , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Histidina/síntesis química , Histidina/química , Histidina/farmacología , Humanos , Estructura Molecular , Compuestos de Fenilurea/química , Factor de Transcripción STAT3/metabolismo , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
A novel tandem metal relay catalytic system was developed by combining gold-catalyzed cycloisomerization with an early transition-metal-catalyzed inverse-electron-demand hetero-Diels-Alder (IED-HDA) reaction. Various biologically important spiroaminals and spiroketals were obtained with very high efficiency under mild conditions.
Asunto(s)
Aminas/síntesis química , Compuestos Organometálicos/química , Compuestos de Espiro/síntesis química , Elementos de Transición/química , Aminas/química , Catálisis , Modelos Moleculares , Estructura Molecular , Compuestos de Espiro/químicaRESUMEN
A novel class of primary amine-metal Lewis acid bifunctional catalysts based on a bidentate ligand was developed. These catalysts were highly efficient in catalyzing the direct asymmetric aldol reactions of ketones offering excellent stereoselectivity. The aldol reactions required a low catalyst loading (2.5 mol%), and were water compatible.
Asunto(s)
Alcoholes/síntesis química , Aldehídos/química , Aminas/química , Cobre/química , Cetonas/química , Alcoholes/química , Catálisis , Ligandos , Estructura Molecular , EstereoisomerismoRESUMEN
The first example of metal Lewis acid-primary amine bifunctional cooperative catalyst derived from primary amino acids was developed, and it was found to catalyze aldol reactions of cyclic ketones highly efficiently with very good to excellent stereoselectivities.