Photoinduced Evolution of Flavanones via C-C Bond Formation for Potent COMT Inhibition

To explore and expand the chemical space of natural products, there is an urgent need for efficient and functional modification of natural products. Here, a photoinduced strategy is reported to access flavanone-based pseudonatural products via late-stage functionalization. This mild procedure enables the chemical evolution of diverse flavanones via introduction of 1,1-diarylalkane scaffolds. The method features mild reaction conditions, operational simplicity, high functional group tolerance, and scalability. Moreover, the cheminformatics results indicate that the pseudonatural products possess excellent drug-like properties and shape diversity. Finally, the catechol-O-methyltransferase (COMT) inhibitory activity analysis demonstrated that compounds 26d and 28d exhibit potent COMT inhibition, with IC₅₀ values of 85.2 and 99.7 nM, respectively, providing valuable insights for the development of novel flavanone-based non-nitrocatechol COMT inhibitors for Parkinson's disease treatment.