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

The biosynthesis of leukotrienes in one of the arachidonic acid pathways and PGE(2) in the other by 5-LOX and mPGES1 respectively, play pivotal roles in augmenting inflammatory responses. PGE(2) 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 M and 63 +/- 0.13 M against 5-LOX and PGE(2) production respectively. Another compound 7f, exhibits an IC50 of 12.4 +/- 0.14 M 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 M against PGE2 production. lc and 7c inhibit the mRNA expression of mPGES1 and COX-2. The study has identified a novel scaffold, lc with a dual inhibitory activity which can be further optimized to compete against Licofelone which is under clinical trials (with IC50 of 6.0 M for mPGES1 & 0.2 M for 5-LOX). To conclude, 3-aryl isocoumarin derivatives appears as promising tools to fight against inflammatory diseases as well as cancer. (C) 2016 Elsevier Masson SAS. All rights reserved.