Fullerenemalonates inhibit amyloid beta aggregation, in vitro and in silico evaluation
The onset of Alzheimer's disease (AD) is associated with the presence of neurofibrillary pathology such as amyloid β (Aβ) plaques. Different therapeutic strategies have focused on the inhibition of Aβ aggregate formation; these pathological structures lead to neuronal disorder and cognitive impairment. Fullerene C60 has demonstrated the ability to interact and prevent Aβ fibril development; however, its low solubility and toxicity to cells remain significant problems. In this study, we synthesized, characterized and compared diethyl fullerenemalonates and the corresponding sodium salts, adducts of C60 bearing 1 to 3 diethyl malonyl and disodium malonyl substituents to evaluate the potential inhibitory effect on the aggregation of Aβ42 and their biocompatibility. The dose-dependent inhibitory effect of fullerenes on Aβ42 aggregation was studied using a thioflavin T fluorescent assay, and the IC50 value demonstrated a low range of fullerene concentration for inhibition, as confirmed by electron microscopy. The exposure of neuroblastoma to fullerenemalonates showed low toxicity, primarily in the presence of the sodium salt-adducts. An isomeric mixture of bisadducts, trisadducts and a C3-symetrical trisadduct demonstrated the highest efficacy among the tests. In silico calculations were performed to complement the experimental data, obtaining a deeper understanding of the Aβ inhibitory mechanism; indicating that C3-symetrical trisadduct interacts mainly with 1D to 16K residues of Aβ42 peptide. These data suggest that fullerenemalonates require specific substituents designed as sodium salt molecules to inhibit Aβ fibrillization and perform with low toxicity. These are promising molecules for developing future therapies involving Aβ aggregates in diseases such as AD and other types of dementia.
- This article is part of the themed collection: Celebrating recent chemical science in Mexico