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

The N-truncated β-amyloid (Aβ) isoform Aβ4–x is known to bind Cu2+ via a redox-silent ATCUN motif with a conditional K d = 30 fM at pH 7.4. This study characterizes the Cu2+ interactions and redox activity of Aβ x–16 (x = 1, 4) and 2-[(dimethylamino)-methyl-8-hydroxyquinoline, a terdentate 8-hydroxyquinoline (8HQ) with a conditional K d(CuL) = 35 pM at pH 7.4. Metal transfer between Cu­(Aβ1–16), CuL, CuL2, and ternary CuL­(NIm Aβ) was rapid, while the corresponding equilibrium between L and Aβ4–16 occurred slowly via a metastable CuL­(NIm Aβ) 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 NIm Aβ ligand will be readily exchangeable with NIm ligands of ubiquitous protein His side chains in vivo, this class of 8HQ ligand could transfer Cu2+ from inert Cu­(Aβ4–x ) to redox-active CuL­(NIm). These findings have implications for the use of terdentate 8HQs as therapeutic chelators to treat neurodegenerative disease.