RESUMEN
The cyclodepsipeptide doliculide is a marine natural product with strong actin-polymerizing and anticancer activities. Evidence for doliculide acting as a potent and subtype-selective antagonist of prostanoidâ E receptor 3 (EP3) is presented. Computational target prediction suggested that this membrane receptor is a likely macromolecular target and enabled immediate inâ vitro validation. This proof-of-concept study demonstrates the inâ silico deorphanization of phenotypic screening hits as a viable concept for future natural-product-inspired chemical biology and drug discovery efforts.
Asunto(s)
Productos Biológicos/metabolismo , Depsipéptidos/metabolismo , Productos Biológicos/química , Depsipéptidos/síntesis química , Depsipéptidos/química , Diseño de Fármacos , Células HEK293 , Humanos , Cinética , Ligandos , Subtipo EP3 de Receptores de Prostaglandina E/antagonistas & inhibidores , Subtipo EP3 de Receptores de Prostaglandina E/genética , Subtipo EP3 de Receptores de Prostaglandina E/metabolismoRESUMEN
The SAR of a series of new epothilone A derivatives with a 2-substituted-1,3-oxazoline moiety trans-fused to the C12-C13 bond of the deoxy macrocycle have been investigated with regard to tubulin polymerization induction and cancer cell growth inhibition. Significant differences in antiproliferative activity were observed between different analogs, depending on the nature of the substituent at the 2-position of the oxazoline ring. The most potent compounds showed comparable activity with the natural product epothilone A. Modeling studies provide a preliminary rationale for the observed SAR.
Asunto(s)
Antineoplásicos/síntesis química , Epotilonas/química , Oxazoles/síntesis química , Moduladores de Tubulina/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular , Simulación por Computador , Humanos , Oxazoles/química , Oxazoles/farmacología , Relación Estructura-Actividad , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologíaRESUMEN
The conformational properties of the microtubule-stabilizing agent epothilone A ( 1a) and its 3-deoxy and 3-deoxy-2,3-didehydro derivatives 2 and 3 have been investigated in aqueous solution by a combination of NMR spectroscopic methods, Monte Carlo conformational searches, and NAMFIS calculations. The tubulin-bound conformation of epothilone A ( 1a), as previously proposed on the basis of solution NMR data, was found to represent a significant fraction of the ensemble of conformations present for the free ligands in aqueous solution.