Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity

Abstract

Multifunctional metal chelators that can modulate the amyloid β (Aβ) peptide aggregation and its interaction with metal ions such as copper and zinc hold considerable promise as therapeutic agents for Alzheimer’s disease (AD). However, specific rather than systemic metal chelation by these compounds is needed in order to limit any side effects. Reported herein are two novel small bifunctional chelators, 2-[2-hydroxy-4-(diethylamino)phenyl]benzothiazole (L1) and 2-(2-hydroxy-3-methoxyphenyl)benzothiazole (L2), in which the metal-binding donor atoms are integrated within a molecular framework derived from the amyloid-binding fluorescent dye thioflavin T (ThT). The metal-binding properties of L1 and L2 were probed by pH spectrophotometric titrations to determine their pKa values and the corresponding metal complex stability constants, and the isolated metal complexes were structurally characterized. The amyloid-fibril-binding properties of L1 and L2 were investigated by fluorescence titrations and ThT competition assays. Interestingly, L1 and L2 do not lead to the formation of neurotoxic Aβ42 oligomers in the presence or absence of metal ions, as observed by native gel electrophoresis, Western blotting, and transmission electron microscopy. In addition, L1 and L2 were able to reduce the cell toxicity of preformed Aβ42 oligomers and of the copper-stabilized Aβ42 oligomers. Given their ability to reduce the toxicity of soluble Aβ42 and Cu-Aβ42 species, L1 and L2 are promising lead compounds for the development of chemical agents that can control the neurotoxicity of soluble Aβ42 species in AD.

Multifunctionality of Acidulated Serum Albumin on Inhibiting Zn2+-Mediated Amyloid β-Protein Fibrillogenesis and Cytotoxicity

“…6,7 Although many studies have investigated the involvement of Zn 2+ in Aβ aggregation, the molecular mechanisms of Zn 2+ −Aβ interactions are still not clearly elucidated. 8 Hence, preventing Zn 2+ −Aβ interactions to inhibit Zn 2+ −Aβ species formation would greatly contribute to the treatment of AD.…”

Self‐Assembly of Tyrosine into Controlled Supramolecular Nanostructures

“…The self‐assembly process is reversible upon complexation of the Tyr structures with copper ions. The chelating ability of Tyr for Cu could be exploited to develop novel copper chelator agents for neuroprotection in Alzheimer’s disease 22. 23 The Tyr‐based supramolecular structures could also find potential applications such as biosensors or molecular scaffolds for regenerative medicine.…”

A small bifunctional chelator that modulates Aβ42 aggregation

“…The broadness of the peak suggests that a mixture of 1:1 and 1:2 metal: ligand species are present in solution at pH 7.4. 46,47 ThT shows an increase in fluorescence in the presence of A␤ 1-42 fibrils 48 and was used to investigate the influence of L1 on the aggregation pattern in the presence and absence of Cu 2+ . PBT2 (Fig.…”