Rewiring the Target Landscape of Bioactive Natural Products by Photocatalytic Single-Atom Editing

Abstract

The natural products provide a foundational chemical space for drug discovery, yet their clinical utility is often constrained by intrinsic liabilities. Skeletal editing, the direct manipulation of individual atoms within a cyclic moiety, has emerged as a strategy for remodeling these compounds, but whether the exchange of a single skeletal heteroatom is sufficient to redirect the pharmacological behavior of a fully elaborated natural product has not been established. Here, we show that the oxygen-to-nitrogen single-atom editing of natural products dramatically rewires their target engagement landscapes. We developed a mild photocatalytic methodology that converts densely functionalized, furan-based terpenoids and alkaloids into their free pyrrole analogues with excellent chemoselectivity. Applying the method to limonin, a cytotoxic citrus triterpenoid, the minimal atomic edit shifts the primary biological target from the canonical kinase pathway engaged by the native molecule to mitochondrial nicotinamide nucleotide transhydrogenase. This target redirection transforms a cytotoxic compound into a potent antifibrotic agent without measurable cytotoxicity up to 80 μM. These findings establish single-atom editing as a transformative strategy for repurposing natural-product scaffolds.