A New Generation of Arachidonic Acid Analogues as Potential Neurological Agent Targeting Cytosolic Phospholipase A2

Cheng Yang Ng,Mei Lin Go,Chian-Ming Low,Wee Yong Ong,Srinivasaraghavan Kannan,Chandra S Verma,Yong Jun Chen,Francis Chee Kuan Tan,Yulin Lam

doi:10.1038/s41598-017-13996-8

Abstract

Cytosolic phospholipase A2 (cPLA2) is an enzyme that releases arachidonic acid (AA) for the synthesis of eicosanoids and lysophospholipids which play critical roles in the initiation and modulation of oxidative stress and neuroinflammation. In the central nervous system, cPLA2 activation is implicated in the pathogenesis of various neurodegenerative diseases that involves neuroinflammation, thus making it an important pharmacological target. In this paper, a new class of arachidonic acid (AA) analogues was synthesized and evaluated for their ability to inhibit cPLA2. Several compounds were found to inhibit cPLA2 more strongly than arachidonyl trifluoromethyl ketone (AACOCF3), an inhibitor that is commonly used in the study of cPLA2-related neurodegenerative diseases. Subsequent experiments concluded that one of the inhibitors was found to be cPLA2-selective, non-cytotoxic, cell and brain penetrant and capable of reducing reactive oxygen species (ROS) and nitric oxide (NO) production in stimulated microglial cells. Computational studies were employed to understand how the compound interacts with cPLA2.

Highlights

To possess brain penetrability[17,18]
The carboxylic acid functionality could be modified to a trifluoromethylketone group to form the well-known Cytosolic phospholipase A2 (cPLA2) inhibitor, AACOCF3
AACOCF3 has been effective in reducing the undesirable effects of dysregulated cPLA2 systems, including those found in neurological diseases[9,24,25,26]

Summary

Introduction

To possess brain penetrability[17,18]. As part of our efforts to develop cPLA2 inhibitors as potential drug candidates for the treatment of neurological disorders, we have synthesized a new series of AA analogues 1–2 and evaluated them for their PLA2 inhibitory activities and ability to cross the BBB. We have focused on the arachidonyl scaffold as earlier studies have shown that this pharmacophore is strongly recognized by cPLA219–23. We present the synthesis of AA analogues 1–2 and the investigation of these compounds for their (i) inhibition of cPLA2, (ii) cytotoxicity, (iii) selectivity and anti-neuroinflammatory properties and (iv) ability to cross the blood-brain barrier; computational studies were performed to understand how the compounds bind to cPLA2

Methods

Results

Conclusion