Synthesis and docking studies of 2,4,6-trihydroxy-3-geranylacetophenone analogs as potential lipoxygenase inhibitor.

Chean Ng,Khozirah Shaari,Intan Ismail,Radhakrishnan Narayanaswamy,Kok Lam,Fadzureena Jamaludin,Faridah Abas,Mohd Aluwi,Kamal Rullah

doi:10.3390/molecules190811645

Abstract

The natural product molecule 2,4,6-trihydroxy-3-geranyl-acetophenone (tHGA) isolated from the medicinal plant Melicope ptelefolia was shown to exhibit potent lipoxygenase (LOX) inhibitory activity. It is known that LOX plays an important role in inflammatory response as it catalyzes the oxidation of unsaturated fatty acids, such as linoleic acid to form hydroperoxides. The search for selective LOX inhibitors may provide new therapeutic approach for inflammatory diseases. Herein, we report the synthesis of tHGA analogs using simple Friedel-Craft acylation and alkylation reactions with the aim of obtaining a better insight into the structure-activity relationships of the compounds. All the synthesized analogs showed potent soybean 15-LOX inhibitory activity in a dose-dependent manner (IC50 = 10.31–27.61 μM) where compound 3e was two-fold more active than tHGA. Molecular docking was then applied to reveal the important binding interactions of compound 3e in soybean 15-LOX binding site. The findings suggest that the presence of longer acyl bearing aliphatic chain (5Cs) and aromatic groups could significantly affect the enzymatic activity.

Highlights

Lipoxygenases (LOXs) are a large monomeric protein family with non-heme, non-sulphur, and iron cofactor containing dioxygenases that catalyze the polyunsaturated fatty acid (PUFA) as a substrate to yield hydroperoxides [1]
Biological evaluation revealed that the three target compounds (3c, 3e and 3g) displayed better activities against soybean15-LOX with IC50 values 12.32 μM, 10.32 μM and 15.20 μM, respectively
Molecular docking studies revealed that the most active compound 3e was found to line in the same cavity of 13-HPOD

Summary

Introduction

Lipoxygenases (LOXs) are a large monomeric protein family with non-heme, non-sulphur, and iron cofactor containing dioxygenases that catalyze the polyunsaturated fatty acid (PUFA) as a substrate to yield hydroperoxides [1]. LOXs from plants and mammals have highest level of sequence identity in the area of catalytic domain containing non-heme iron atom [2]. The common substrates of animals (arachidonic acid, 20-carbon) and plants (linoleic and α-linoleic acids, 18-carbon) differ in their chain lengths [4]. Mammalian LOXs catalyze the conversion of arachidonic acid to form hydroperoxy eicosatetraenoic acids (HPETEs) via radical mechanism [5]. LOX from plants oxygenate linoleic acid to generate 13-hydroperoxy-9(Z),11(E)octadecadienoic acid (13-HPOD) [6]

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Results

Conclusion