Design of Diarylheptanoid Derivatives as Dual Inhibitors Against Class IIa Histone Deacetylase and β-amyloid Aggregation

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with multiple etiologies. Beta-amyloid (Aβ) self-aggregation and overexpression of class IIa histone deacetylases (HDACs) are strongly implicated with AD pathogenesis. In this study, a series of novel diarylheptanoid derivatives were designed, synthesized and evaluated for use as dual Aβ self-aggregation and class IIa HDAC inhibitors. Among these compounds, 4j, 5c, and 5e displayed effective inhibitions for Aβ self-aggregation, HDAC5 activity and HDAC7 activity with IC50 values of <10 μM. The compounds contain three common features: (1) a catechol or pyrogallol moiety, (2) a carbonyl linker and (3) an aromatic ring that can function as an HDAC cap and create hydrophobic interactions with Aβ1-42. Furthermore, compounds 4j, 5c, and 5e showed no significant cytotoxicity to human neuroblastoma SH-SY5Y cells and also exhibited neuroprotective effect against H2O2-induced toxicity. Overall, these promising in vitro data highlighted compounds 4j, 5c, and 5e as lead compounds that are worthy for further investigation.

Synthesis and biological evaluation of C-4 substituted phenoxazine-bearing hydroxamic acids with potent class II histone deacetylase inhibitory activities

“…Cell viability was assessed using the alamar blue (7-hydroxy-10-oxidophenoxazin-10-ium-3-one) assay in six replicates as described previously 29 . Briefly, 5 × 10 3 cells/well were seeded in 96-well flat-bottomed plates; 24 h later, cells were treated with compounds or DMSO as control.…”

“…H 2 O 2 -induced neurotoxicity on SH-SY5Y cells was used to evaluate the neuroprotective effect 29 . Briefly, a density of 2 × 10 4 SH-SY5Y cells was seeded per well in 96-well plates.…”

Inhibition of Acetylcholinesterase and Amyloid-β Aggregation by Piceatannol and Analogs: Assessing In Vitro and In Vivo Impact on a Murine Model of Scopolamine-Induced Memory Impairment

“…Docking analysis was performed using the computational software Discovery Studio (DS), a BIOVIA software product, to analyze the molecular modeling, following a previous report [34,39]. The CDOCKER program in DS was used for the molecular docking of AChE and the Aβ peptide .…”

Synthesis of Yakuchinone B-Inspired Inhibitors against Islet Amyloid Polypeptide Aggregation

“…Zingiberaceae herbs are traditionally used for treating various diseases: inflammation, jaundice, diabetes, diarrhea, coryza, dermatosis disorders, and rheumatism. , Alpinia oxyphylla , a traditional Chinese herb, belongs to the Zingiberaceae family. Its fruit contains yakuchinone B, which is a diarylhepanoid. , Recently, we developed yakuchinone B-derived diarylhepanoid 1 , which exhibits inhibitory activity against amyloid β (Aβ) aggregation . In addition to Aβ, the compound also exhibits potent amylin aggregation-inhibiting activity.…”