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

• Published in: European journal of medicinal chemistry 2016-11, Vol.124, p.428-434
• Main Authors: Ramanan, Meera, Sinha, Shweta, Sudarshan, Kasireddy, Aidhen, Indrapal Singh, Doble, Mukesh
• Format: Article
• Language: English
• Subjects: 5-Lipoxygenase; Arachidonate 5-Lipoxygenase - genetics; Arachidonate 5-Lipoxygenase - metabolism; Arachidonic Acid - pharmacology; Cytokines - genetics; Dinoprostone - biosynthesis; Free Radicals - metabolism; Gene Expression Regulation, Enzymologic - drug effects; HeLa Cells; Humans; Inflammation; Inflammation - enzymology; Inflammation - genetics; Inflammation - metabolism; Isocoumarins; Isocoumarins - chemical synthesis; Isocoumarins - chemistry; Isocoumarins - metabolism; Isocoumarins - pharmacology; Kinetics; Leukotrienes - metabolism; Lipoxygenase Inhibitors - chemical synthesis; Lipoxygenase Inhibitors - chemistry; Lipoxygenase Inhibitors - metabolism; Lipoxygenase Inhibitors - pharmacology; Microsomal prostaglandin E2 synthase 1; Prostaglandins - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.08.066

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. [Display omitted] •3-(3, 4-dihydroxyphenyl)-1H-isochromen-1-one (1c) inhibits 5-LOX and PGE2 in the arachidonic acid pathway.•The mechanism of inhibition of 5-LOX by 1c is through redox process.•1c also masks the mRNA expression of COX-2 and mPGES1.