RESUMEN
Natural products provide evolutionary validated core structures to inspire the synthesis of new compound collections endowed with neurite growth-promoting activity. Rhynchophylline is the major component of Uncaria species, and has been used to treat neurological diseases in Chinese traditional medicine. Based on the structure of this spirocyclic secoyohimbane alkaloid, we developed a highly enantioselective and efficient organocatalyzed synthesis method to provide a tetracyclic secoyohimbane scaffold incorporating a quaternary and three tertiary stereogenic centers, in a one-pot multistep reaction sequence. A compound collection of derived secoyohimbanes was synthesized and expanded by decorating the periphery of the basic scaffold with additional substituents to increase the diversity. Evaluation of the different subcollections of secoyohimbanes for modulation of neurite outgrowth in the SH-SY5Y human cell line led to the discovery of new compounds that promote neurite outgrowth.
Asunto(s)
Alcaloides Indólicos/síntesis química , Proyección Neuronal/efectos de los fármacos , Fármacos Neuroprotectores/síntesis química , Compuestos de Espiro/síntesis química , Uncaria/química , Catálisis , Línea Celular Tumoral , Técnicas de Química Sintética , Humanos , Alcaloides Indólicos/aislamiento & purificación , Alcaloides Indólicos/farmacología , Estructura Molecular , Neuronas/citología , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/aislamiento & purificación , Fármacos Neuroprotectores/farmacología , Oxindoles , Compuestos de Espiro/aislamiento & purificación , Compuestos de Espiro/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Cousins you can count on: An iridoid-inspired compound collection was synthesized efficiently by the resolution of cyclic enones in an asymmetric cycloaddition with azomethine ylides. The collection contained novel potent inhibitors of the Wnt and Hedgehog signaling pathways.
Asunto(s)
Proteínas Hedgehog/metabolismo , Iridoides/química , Iridoides/farmacología , Transducción de Señal/efectos de los fármacos , Proteínas Wnt/metabolismo , Animales , Catálisis , Línea Celular , Supervivencia Celular/efectos de los fármacos , Reacción de Cicloadición , Evaluación Preclínica de Medicamentos , Células HEK293 , Proteínas Hedgehog/antagonistas & inhibidores , Humanos , Iridoides/síntesis química , Ratones , Estereoisomerismo , Relación Estructura-Actividad , Proteínas Wnt/antagonistas & inhibidoresRESUMEN
Lipocalin 24p3 plays a direct role in iron transport and regulates the levels of important proteins of the iron metabolism. Iron-loaded 24p3 binds to its specific receptor (24p3R) on the cell surface. Upon binding to its receptor, 24p3 is internalized into the cell, where it releases its bound iron. Iron-free 24p3 can withdraw iron from inside the cell to the outside by a reverse mechanism. We analyzed the role of the murine 24p3 gene Lcn2 (alias 24p3) as a target of the Wnt pathway. In cells with activated Wnt pathway, the levels of 24p3 protein and RNA were decreased. The withdrawal of iron led to 24p3 downregulation, and iron addition to iron-deprived cells induced 24p3 expression. Despite its strong inhibitory effect on 24p3 expression, Wnt pathway activation had no effect on the intracellular iron level. In cells with nonactivated Wnt pathway, we found an as yet unidentified transcript of 24p3R. Our results indicate independent regulation of 24p3 expression by the Wnt pathway and by the intracellular iron level. Differential splicing of the 24p3R transcript, depending on the activation state of the Wnt pathway, may modify the function of 24p3.