Relationship between the tautomeric structures of curcumin derivatives and their Aβ-binding activities in the context of therapies for Alzheimer's disease

Abstract

Curcumin, which can exist in an equilibrium between keto and enol tautomers, binds to β-amyloid (Aβ) fibrils/aggregates. The aim of this study was to assess the relationship between the tautomeric structures of curcumin derivatives and their Aβ-binding activities. Curcumin derivatives with keto-enol tautomerism showed high levels of binding to Aβ aggregates but not to Aβ monomers. The binding activity of the keto form analogue of curcumin to Aβ aggregates was found to be much weaker than that of curcumin derivatives with keto-enol tautomerism. The color of a curcumin derivative with keto-enol tautomerism, which was substituted at the C-4 position, changed from yellow to orange within 30 min of being combined with Aβ aggregates in physiological buffer. This resulted from a remarkable increase in the enol form with extended conjugation of double bonds upon binding. These findings suggest that curcumin derivatives exist predominantly in the enol form during binding to Aβ aggregates, and that the enolization of curcumin derivatives is crucial for binding to Aβ aggregates. The keto-enol tautomerism of curcumin derivatives may be a novel target for the design of amyloid-binding agents that can be used both for therapy and for amyloid detection in Alzheimer's disease.