ABSTRACT
So far monotargeted therapies in Alzheimers disease (AD) led to insufficient results. Slight improvements in the AD symptomatics have been limited to patients in the early stage of the disease. So multitargeting approaches have been started addressing amyloid plaques as preferred primary target structures beside acetylcholine esterase inhibition. Various protein kinases have been discussed to make a contribution to the progression of AD. So protein kinases are promising target structures for a perspective multitargeting. We identified substituted smallmolecule protein kinase inhibitors of the tricyclic benzofuropyridine type which showed partly nanomolar affinities to AD-relevant glycogen synthase kinase (gsk) 3ß, extracellular-signal regulated kinase (ERK) 2 and C-Jun-N-terminal kinase (JNK) 3. Substituent-dependent effects on the respective kinase inhibitions are discussed and inhibitor binding modes to those kinases are presented based on enzyme docking studies. Inhibitor effects on the tau protein target structure are shown for first compounds in cellular studies to prove the enzyme conditioned effects.
Subject(s)
Alzheimer Disease/enzymology , Enzyme Inhibitors/chemistry , Glycogen Synthase Kinase 3 beta/metabolism , tau Proteins/metabolism , Alzheimer Disease/drug therapy , Animals , COS Cells , Chlorocebus aethiops , Drug Discovery , Enzyme Inhibitors/pharmacology , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , Mitogen-Activated Protein Kinase 6/metabolism , Phosphorylation/drug effects , Transfection , tau Proteins/drug effectsSubject(s)
Carcinoma, Hepatocellular/complications , Hepatitis C, Chronic/complications , Antiviral Agents/therapeutic use , Carcinoma, Hepatocellular/blood , Carcinoma, Hepatocellular/diagnosis , Hepacivirus/drug effects , Hepacivirus/isolation & purification , Hepatitis C, Chronic/blood , Hepatitis C, Chronic/drug therapy , Humans , Interferon alpha-2 , Interferon-alpha/therapeutic use , Liver Function Tests , Recombinant Proteins , Ribavirin/therapeutic use , Treatment Outcome , Viral LoadABSTRACT
Se estudia la actividad celulolítica de cepas de aspergillus niger y a. flavus aisladas de suelo del sur de la provincia de Santa Fe, sembrado con trigo y tratado con metsulfurón-metil+dicamba. Dichas cepas fueron las más frecuentes en un muestreo que abarcó distintas etapas del cultivo de trigo en 1994 y mostraron a su vez, variaciones en su frecuencia a lo largo del mismo. Nuestro objetivo fue conocer si dichas variaciones de frecuencia se correlacionaron con cambios en la actividad celulolítica de las mismas. Se trabajó con tres cepas de a. niger y dos de a. flavus. En los filtrados de los cultivos, se determinó: peso seco, proteínas solubles, producción de exoglucanasas frente a la celulosa cristalina, endoglucanasas frente a carboximetilcelulosa y celobiasis extracelulares. En a. niger, no hubo una correlación clara entre frecuencia y actividad enzimática, sólo se obserbó que las cepas de a. niger de mayor frecuencia (superior al 50 porciento) tuvieron también mayor actividad. En a. flavus, en cambio, se observó una correlación diversa.
