Copper Exchange and Redox Activity of a Prototypical 8-Hydroxyquinoline: Implications for Therapeutic Chelation

Abstract

The N-truncated β-amyloid (Aβ) isoform Aβ4-x is known to bind Cu2+ via a redox-silent ATCUN motif with a conditional Kd = 30 fM at pH 7.4. This study characterizes the Cu2+ interactions and redox activity of Aβx-16 (x = 1, 4) and 2-[(dimethylamino)-methyl-8-hydroxyquinoline, a terdentate 8-hydroxyquinoline (8HQ) with a conditional Kd(CuL) = 35 pM at pH 7.4. Metal transfer between Cu(Aβ1-16), CuL, CuL2, and ternary CuL(NImAβ) was rapid, while the corresponding equilibrium between L and Aβ4-16 occurred slowly via a metastable CuL(NImAβ) intermediate. Both CuL and CuL2 were redox-silent in the presence of ascorbate, but a CuL(NIm) complex can generate reactive oxygen species. Because the NImAβ ..