RESUMEN
The oral microbiome is a dynamic environment inhabited by both commensals and pathogens. Among these is Streptococcus mutans, the causative agent of dental caries, the most prevalent childhood disease. Carolacton has remarkably specific activity against S. mutans, causing acid-mediated cell death during biofilm formation; however, its complex structure limits its utility. Herein, we report the diverted total synthesis and biological evaluation of a rationally designed library of simplified analogs that unveiled three unique biofilm phenotypes further validating the role of natural product synthesis in the discovery of new biological phenomena.
Asunto(s)
Biopelículas/efectos de los fármacos , Productos Biológicos/farmacología , Macrólidos/farmacología , Streptococcus mutans/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Productos Biológicos/síntesis química , Productos Biológicos/química , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Macrólidos/síntesis química , Macrólidos/química , Estructura Molecular , Tamaño de la Partícula , Fenotipo , Streptococcus mutans/citología , Streptococcus mutans/metabolismo , Relación Estructura-Actividad , Propiedades de SuperficieRESUMEN
Natural products commonly produced as secondary metabolites of various plants and micro-organisms represent a diverse chemical space of compounds. The diversity of natural products makes them an attractive target for interrogation by both chemists and biologists alike. Indeed, the study of 12-membered macrolactones has already led to the discovery of lead drug compounds and new biological targets, which has motivated the development of diverted total synthetic routes to libraries of analogs. This review explores the discovery, biological characterization, and synthesis of several 12-membered macrolactones, exploiting examples that underscore their importance in the drug discovery field. It is our hope that this review will motivate further interest in this class of natural products, a group of molecules that we think merit the classification of 'privileged scaffolds' within the medicinal chemistry community, to further investigate and develop novel compounds with promising bioactivity.
Asunto(s)
Descubrimiento de Drogas , Lactonas/síntesis química , Productos Biológicos/química , Humanos , Macrólidos/síntesis química , Macrólidos/químicaRESUMEN
A synthesis of carolacton, a myxobacterial natural product that has profound effects on Streptococcus mutans biofilms, is reported. The synthesis proceeds via a longest linear sequence of 14 steps from an Evans ß-ketoimide and enabled preliminary evaluations of the effects of late-stage intermediates on S. mutans biofilms. These studies suggest that further investigations into carolacton's structure-function relationships are warranted.