2. Academic Validation
  3. Inhibition of the enzymes in the leukotriene and prostaglandin pathways in inflammation by 3-aryl isocoumarins

Inhibition of the enzymes in the leukotriene and prostaglandin pathways in inflammation by 3-aryl isocoumarins

  • Eur J Med Chem. 2016 Nov 29:124:428-434. doi: 10.1016/j.ejmech.2016.08.066.
Meera Ramanan 1,  Shweta Sinha 1,  Kasireddy Sudarshan 2,  Indrapal Singh Aidhen 3,  Mukesh Doble 4
Affiliations

Affiliations

  • 1 Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology, Madras, Tamil Nadu, 600036, India.
  • 2 Department of Chemistry, Indian Institute of Technology, Madras, Tamil Nadu, 600036, India.
  • 3 Department of Chemistry, Indian Institute of Technology, Madras, Tamil Nadu, 600036, India. Electronic address: isingh@iitm.ac.in.
  • 4 Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology, Madras, Tamil Nadu, 600036, India. Electronic address: mukeshd@iitm.ac.in.
PMID: 27597418 DOI: 10.1016/j.ejmech.2016.08.066
Abstract

The biosynthesis of leukotrienes in one of the arachidonic acid pathways and PGE2 in the Other by 5-LOX and mPGES1 respectively, play pivotal roles in augmenting inflammatory responses. PGE2 is known to participate in Cancer pathological processes as well. Isocoumarins are natural compounds with a wide range of biological activities. In this study, 3-aryl isocoumarin derivatives are synthesized and tested against 5-LOX Enzyme in vitro and PGE2 production in HeLa cells. Most of the compounds show high activity, and 1c is identified as a dual inhibitor with an IC50 of 4.6 ± 0.26 μM and 6.3 ± 0.13 μM against 5-LOX and PGE2 production respectively. Another compound 7f, exhibits an IC50 of 12.4 ± 0.14 μM against 5-LOX. Further investigations reveal that the mechanism of action of 1c and 7f against 5-LOX is mixed and competitive modes of action respectively. Thunberginol A (7c) exhibits IC50 of 15.8 ± 0.03 μM against PGE2 production. 1c and 7c inhibit the mRNA expression of mPGES1 and COX-2. The study has identified a novel scaffold, 1c with a dual inhibitory activity which can be further optimized to compete against Licofelone which is under clinical trials (with IC50 of 6.0 μM for mPGES1 & 0.2 μM for 5-LOX). To conclude, 3-aryl isocoumarin derivatives appears as promising tools to fight against inflammatory diseases as well as Cancer.

Keywords

5-Lipoxygenase; Inflammation; Isocoumarins; Microsomal prostaglandin E(2) synthase 1.

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