Lactone-to-lactam editing alters the pharmacology of bilobalide

Precise transformations of natural products (NPs) can fine-tune their physicochemical properties while preserving inherently complex and evolutionarily optimized parent scaffolds. Here, we report an unprecedented lactone-to-lactam transformation on bilobalide, thus improving its stability and paving the way for biological exploration of previously inaccessible chemical space that is highly representative of the parent structure. This late-stage molecular editing of bilobalide enables facile access to a unique library of lactam analogues with altered pharmacology. Through phenotypic screening, we identify BB10 as a hit compound with unexpected inhibition of ferroptotic cell death. We further reveal that BB10 suppresses ferroptosis by restoring the expression of glutathione peroxidase 4 (GPX4) in brain cells. This study highlights that even subtle changes on NP scaffolds can confer new pharmacological properties, inspiring the exploration of simple yet critical transformations on complex NPs.

JACS Au 2024, 4, 9, 3537–3546