Copper(II) Coordination and Translocation in Luteolin and Effect on Radical Scavenging

Luteolin differs as a radical scavenger dramatically from apigenin in response to Cu­(II) coordination despite a minor structural difference. Coordination of Cu­(II) increases the radical scavenging efficiency of luteolin, especially at low pH, while decreases the efficiency of apigenin at both low and higher pH as studied by ABTS•+ radical scavenging. Luteolin forms a 1:1 complex with Cu­(II) binding to 4-carbonyl and 5-phenol for pH 6. Apigenin forms a 1:2 complex independent of pH coordinated to 4-carbonyl and 5-hydroxylyl. Cu­(II) coordinated to luteolin, as studied by pH jump stopped-flow, translocates with rate constants of 11.1 ± 0.3 s–1 from 4,5 to 3′,4′ sites and 1.0 ± 0.1 s–1 from 3′,4′ to 4,5 sites independent of Cu­(II) concentration, pointing toward the dissociation of Cu­(II) from an intermediate with two Cu­(II) coordination as rate determining. 3′,4′-Catechol is suggested to be a switch for Cu­(II) translocation with deprotonation initiating 4,5 to 3′,4′ translocation and protonation initiating 3′,4′ to 4,5 translocation. For dicoordinated apigenin, the coordination symmetry balances an electron withdrawal effect of Cu­(II) resulting in a decrease of phenol acidity and less radical scavenging efficiency compared to parent apigenin. Compared to that of parent luteolin, the radical scavenging rate of both 4,5 and 3′,4′ Cu­(II)-coordinated luteolin is enhanced through increased phenol acidity by electron withdrawal by Cu­(II), as confirmed by density functional theory (DFT) calculations. Coordination and translocation of Cu­(II) accordingly increases the antioxidant activity of luteolin at pH approaching the physiological level and is discovered as a novel class of natural molecular machinery derived from plant polyphenols, which seems to be of importance for protection against oxidative stress.