2 research outputs found
Total Synthesis of Hispidulin and the Structural Basis for Its Inhibition of Proto-oncogene Kinase Pim‑1
A new method is applied to synthesize
hispidulin, a natural flavone
with a broad spectrum of biological activities. Hispidulin exhibits
inhibitory activity against the oncogenic protein kinase Pim-1. Crystallographic
analysis of Pim-1 bound to hispidulin reveals a binding mode distinct
from that of quercetin, suggesting that the binding potency of flavonoids
is determined by their hydrogen-bonding interactions with the hinge
region of the kinase. Overall, this work may facilitate construction
of a library of hispidulin-derived compounds for investigating the
structure–activity relationship of flavone-based Pim-1 inhibitors
Data_Sheet_1_Design of Diarylheptanoid Derivatives as Dual Inhibitors Against Class IIa Histone Deacetylase and β-amyloid Aggregation.PDF
<p>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 IC<sub>50</sub> 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 Aβ<sub>1-42</sub>. Furthermore, compounds 4j, 5c, and 5e showed no significant cytotoxicity to human neuroblastoma SH-SY5Y cells and also exhibited neuroprotective effect against H<sub>2</sub>O<sub>2</sub>-induced toxicity. Overall, these promising in vitro data highlighted compounds 4j, 5c, and 5e as lead compounds that are worthy for further investigation.</p