Copper(I) Chelators for Alzheimer’s Disease

Abstract

A component of the neurotoxicity of the beta amyloid peptide (Aβ) of Alzheimer's disease is its ability to generate superoxide, hydrogen peroxide, and hydroxyl radicals by reaction of its reduced copper complex Aβ/Cu with molecular oxygen. The objective of the present work was to devise compounds, L, that could remove Cu from Aβ/Cu, with the property that L/Cu itself would not be capable of reducing O or hydrogen peroxide. We show by density functional calculations that several pincer-type compounds with two imidazole rings and a sulfur or nitrogen have the desired combination of Cu binding affinity and Cu reduction potential.

Pseudopeptide Designed to Inhibit Oligomerization and Redox Chemistry in Alzheimer’s Disease

“…SGC1, though a potential β-sheet blocker, cannot stop copper binding to Rec. Ab initio electronic structure calculations on the dihistidine region of Rec, His 13 His 14 , indicated that Rec (and Aβ) would bind Cu­(II) and Cu­(I) with high affinity, Δ G bind = −55 kJ mol –1 and Δ G bind = −73 kJ mol –1 , respectively, with computed reduction potential, E o = 0.39 V vs NHE . These values are in acceptable agreement with experimental values for Aβ(1–40) and Aβ(1–16), Δ G bind = −50 to −60 kJ mol –1 and Δ G bind = −83 to −85 kJ mol –1 , for Cu­(II) and Cu­(I), respectively, with measured reduction potential, E o = 0.30 V vs NHE .…”

“…A previously designed 35 Cu + chelator, PI1, was elaborated by addition of a carboxylic acid amide group in the 4-position, yielding 4PI1. We showed by DFT calculations that 4PI1 when attached to a Glu residue, has high binding affinity for both Cu + and Cu 2+ , and a low-enough redox potential to prevent the generation of ROS (Figure 3c).…”

“…This involved two positively charged residues at the Cterminus, ornithine (designated OrnH 37 for Cu(II) and Cu(I), respectively, with measured reduction potential, E o = 0.30 V vs NHE. 38 In our previous paper, 35 some ligands that have strong affinity for Cu + and Cu 2+ , and favorable redox properties had been designed, with the intention of attaching one to SGC1 to create a multifunctional ligand, TGC1, to combat Alzheimer's disease. One of the ligands, PI1 (Figure 3a), has properties in the correct range, ΔG bind = −55 kJ mol −1 and ΔG bind = −65 kJ mol −1 , respectively, with computed reduction potential, E o = 0.31 V vs NHE, and was deemed suitable for further development.…”

“…PI1 was modified to 4PI1 (Figure b) by addition of a carboxylic acid amide group to the para position of the pyridine ring for attachment to the N-terminal Glu residue of SGC1. The copper binding and redox properties of 4PI1 were evaluated by the procedures previously described: using Gaussian 16, geometry optimization and frequency analysis was carried out at the CAM-B3LYP/6-31G­(d) level, and the free energy of solvation determined at the same level with SCRF = IPCM (first iteration) . The energy was further determined by single point re-evaluation with the larger basis set, 6-311+G­(2df,2p).…”

Inhibition of Amyloid Beta Aggregation and Deposition of Cistanche tubulosa Aqueous Extract

“…Metal ions were recently considered a key factor closely related with Aβ aggregation [10]. Metal chelators regarded as potential lead compounds provide a whole new strategy for anti-AD approach [9,11,12,13,14,15].…”