Synthesis of Nontoxic Protoflavone Derivatives through Selective Continuous-Flow Hydrogenation of the Flavonoid B-Ring

Protoflavones are unique natural flavonoids with a non-aromatic B-ring, known for their potent antitumor properties. However, their cytotoxicity represents a strong limitation in the further exploration of their pharmacological potential. In the current study, we sought to selectively saturate the p-quinol Bring of protoapigenone and that of its 1'-O-butyl ether, in order to obtain non-toxic protoflavone analogues expressing the dihydro-or tetrahydroprotoflavone structure also occurring in nature. The benefits of a strictly controlled continuous-flow environment in combination with on-demand electrolytic H-2 gas generation were exploited to suppress undesired side reactions and to safely and selectively yield the desired substances. The obtained tetrahydroprotoflavones were free of the cytotoxicity of their parent compounds, and, even though tetrahydroprotoapigenone 1-O-butyl ether showed a weak inhibition of DNA damage response through Chk1, neither compounds influenced the cytotoxicity of doxorubicin either.