Structural Optimization and Biological Evaluation of Substituted Bisphenol A Derivatives as β-Amyloid Peptide Aggregation Inhibitors

Abstract

The aggregation of Abeta is a crucial step in the etiology of Alzheimer's disease. Our previous work showed that Abeta undergoes alpha-helix/beta-sheet intermediate structures during the conformational transition, and an Abeta aggregation inhibitor (1) was discovered by targeting the intermediates. Here, structure optimization toward compound 1 was performed and 34 novel derivatives were designed and synthesized. Nine compounds showed more effective inhibitory activity than the hit compound 1 in ThT fluorescence assay. Among them, compound 43 demonstrated more excellent inhibitory potency, which not only can suppress the aggregation of Abeta but also can dissolve the preformed fibrils as shown by CD spectroscopy, PICUP and AFM assays. Cellular assay indicated that 43 has no toxicity to neuronal cells, moreover, can effectively inhibit Abeta(1-42)-induced neutrotoxicity and increase the cell viability. Together, on the basis of these positive results, these novel chemical structures may provide a promising potential for therapeutic applications in AD and other types of neurodegenerative disorders.

Amyloid beta: structure, biology and structure-based therapeutic development

“…Resveratrol, curcumin, EGb761, isoliquiritigenin, protocatechuic acid, atractylenolide III, chlorogenic acid, euphorbiafactor L3, euphorbiafactor L2, ganoderic acid D, and ganoderic acid DM extracts from Chinese herbal medicine can inhibit Aβ aggregation [303,304] . A series of substituted bisphenol A derivatives function as Aβ aggregation inhibitors and can inhibit neurotoxicity and increase cell viability [305] ( Table 6). …”

Synthesis of Renewable Bisphenols from Creosol

“…[12] HCl (2.5 m) was determined to be the most effective catalyst for the condensation of 1 with formaldehyde. [13] In contrast to the zinccatalyzed reaction, formaldehyde coupled almost exclusively at the position meta to the hydroxyl group with a selectivity of 97 %.…”

“…Turning to Brønsted acid catalysts, we explored the use of biphasic systems consisting of a mineral acid, an aldehyde, and a stoichiometric amount of 1 (Scheme 4). [12] HCl (2.5 m) was determined to be the most effective catalyst for the condensation of 1 with formaldehyde. [13] In contrast to the zinccatalyzed reaction, formaldehyde coupled almost exclusively at the position meta to the hydroxyl group with a selectivity of 97 %.…”

Inhibition of amyloid-β aggregation by coumarin analogs can be manipulated by functionalization of the aromatic center

“…[6][7][8] In particular, compounds containing aromatic centers are capable of preventing the assembly of monomeric Ab into amyloid fibrils. 7,9,10 These compounds are hypothesized to interact with aromatic residues within the hydrophobic core of Ab [11][12][13][14][15] and to inhibit aggregation by disrupting pstacking of these aromatic residues, which is proposed to play a key role in amyloid aggregate formation and growth. 11 Less is known, however, about how the functionalization of aromatic centers can influence inhibitory capabilities.…”