Synthesis and Biological Assessment of Eucalyptin: Magic Methyl Effects.

Abstract

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 <i>O</i>-methylated flavonoids, which show differences in physical and chemical properties from those of unmethylated flavonoids-<i>O</i>-methylation converts the hydrophilic hydroxy group into a hydrophobic methoxy group. However, differences in the physical and chemical properties between <i>C</i>-methylated and unmethylated flavonoids are smaller than those for <i>O</i>-methylated flavonoids. Therefore, predicting the magic methyl effect in <i>C</i>-methylated flavonoids is challenging. Eucalyptin and 8-desmethyleucalyptin are <i>C</i>-methylated flavonoids isolated from the leaves of plants, such as <i>Eucalyptus</i> sp. and <i>Kalmia latifolia</i>. These compounds contain 5-hydroxy-7,4'-dimethoxyflavone as the core skeleton. Eucalyptin has two <i>C</i>-methyl groups at the C-6 and C-8 positions, whereas 8-desmethyleucalyptin has one <i>C</i>-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 <i>C</i>-methylated flavonoids.