2 research outputs found
One-Step Semisynthesis of Oleacein and the Determination as a 5‑Lipoxygenase Inhibitor
The dialdehydes oleacein (<b>2</b>) and oleocanthal (<b>4</b>) are closely related to oleuropein
(<b>1</b>) and
ligstroside (<b>3</b>), the two latter compounds being abundant
iridoids of <i>Olea europaea</i>. By exploiting oleuropein
isolated from the plant leaf extract, an efficient procedure has been
developed for a one-step semisynthesis of oleacein under Krapcho decarbomethoxylation
conditions. Highlighted is the fact that 5-lipoxygenase is a direct
target for oleacein with an inhibitory potential (IC<sub>50</sub>:
2 μM) more potent than oleocanthal (<b>4</b>) and oleuropein
(<b>1</b>). This enzyme catalyzes the initial steps in the biosynthesis
of pro-inflammatory leukotrienes. Taken together, the methodology
presented here offers an alternative solution to isolation or total
synthesis for the procurement of oleacein, thus facilitating the further
development as a potential anti-inflammatory agent
Indirubin Core Structure of Glycogen Synthase Kinase‑3 Inhibitors as Novel Chemotype for Intervention with 5‑Lipoxygenase
The
enzymes 5-lipoxygenase (5-LO) and glycogen synthase kinase
(GSK)-3 represent promising drug targets in inflammation. We made
use of the bisindole core of indirubin, present in GSK-3 inhibitors,
to innovatively target 5-LO at the ATP-binding site for the design
of dual 5-LO/GSK-3 inhibitors. Evaluation of substituted indirubin
derivatives led to the identification of (3<i>Z</i>)-6-bromo-3-[(3<i>E</i>)-3-hydroxyiminoindolin-2-ylidene]Âindolin-2-one (<b>15</b>) as a potent, direct, and reversible 5-LO inhibitor (IC<sub>50</sub> = 1.5 μM), with comparable cellular effectiveness
on 5-LO and GSK-3. Together, we present indirubins as novel chemotypes
for the development of 5-LO inhibitors, the interference with the
ATP-binding site as a novel strategy for 5-LO targeting, and dual
5-LO/GSK-3 inhibition as an unconventional and promising concept for
anti-inflammatory intervention