Structure-dependent membrane interaction of flavonoids associated with their bioactivity

Plant foods contain various flavonoids with nutraceutical and health benefits. Structurally different flavonoids were compared by the potency to interact with liposomal membranes in the context of their mode of action. A series of fluorescence polarisation measurements showed that flavonoids (1–10 μM) structure-dependently acted on the deeper regions of lipid bilayers to decrease membrane fluidity. Their comparative effects on cell-mimetic membranes, consisting of unsaturated phospholipids and cholesterol, characterised the structure–membrane interactivity relationship: 3-hydroxylation of the C ring, non-modification of the B ring and 5,7-dihydroxylation of the A ring led to the greatest membrane interactivity, followed by 3′,4′-dihydroxylation of the B ring. Galangin and quercetin, meeting such a structural requirement, inhibited the proliferation of tumour cells at 10–100 μM, together with rigidifying cell membranes, but not membrane-inactive flavonoids. The structure-dependent membrane interaction, which modifies the fluidity, is mechanistically associated with flavonoid bioactivity in a membranous lipid phase.