Bio-guided Natural Product Drug Discovery Platform Focused on All-Carbon Spirocenter Containing Molecules

Abstract

Natural products remain a vibrant source of novel compounds that can serve as molecular probes or therapeutic agents. Of specific interest among biologically active terrestrial natural products are spirocycles, which are characterized by either a tertiary or quaternary carbon spirocenter. Intrigued by the potential of these natural products as potential wound healing agents, we began a campaign to isolate, characterize, and develop methodologies towards such spirocycle molecules. Herein, we disclose our findings featuring the natural product pteropodine, a pentacyclic oxindole with a spirocenter, as the inspiration to develop spirocycle methodologies. We have successfully isolated pteropodine from the plant Uncaria tomentosa and utilized this natural product as a potential lead. We also developed new methodologies to access these spirocycles after hypothesizing that a metal-mediated ene-type reaction could proceed under mild reaction conditions and tolerate a broad range of substituents to provide functionalized structures. The chemical reactions were carried out under inert atmosphere, monitored by thin layer chromatography, and analyzed by Mass Spectrometry and Nuclear Magnetic Resonance. The biological properties of these compounds in a gap closure migration assay are presented.