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

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.