Synthesis and Biological Assessment of Eucalyptin: Magic Methyl Effects

A drastic alteration in the potency or efficacy of bioactive compounds due to the addition of a single methyl group is known as the magic methyl effect. This effect has been demonstrated in O-methylated flavonoids, which show differences in physical and chemical properties from those of unmethylated flavonoids—O-methylation converts the hydrophilic hydroxy group into a hydrophobic methoxy group. However, differences in the physical and chemical properties between C-methylated and unmethylated flavonoids are smaller than those for O-methylated flavonoids. Therefore, predicting the magic methyl effect in C-methylated flavonoids is challenging. Eucalyptin and 8-desmethyleucalyptin are C-methylated flavonoids isolated from the leaves of plants, such as Eucalyptus sp. and Kalmia latifolia. These compounds contain 5-hydroxy-7,4′-dimethoxyflavone as the core skeleton. Eucalyptin has two C-methyl groups at the C-6 and C-8 positions, whereas 8-desmethyleucalyptin has one C-methyl group at the C-6 position. In this study, we synthesized eucalyptin and assessed its biological activities. The C-8 methyl group caused significant alterations in cytotoxic and antibiofilm activities. Herein, we report the magic methyl effects in eucalyptin, providing a basis for further chemical and biological studies on C-methylated flavonoids.