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 PGE2in the other by 5-LOX and mPGES1 respectively, play pivotal roles in augmenting inflammatory responses. PGE2is 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 PGE2production in HeLa cells. Most of the compounds show high activity, and 1c is identified as a dual inhibitor with an IC50of 4.6 ± 0.26 μM and 6.3 ± 0.13 μM against 5-LOX and PGE2production respectively. Another compound 7f, exhibits an IC50of 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 IC50of 15.8 ± 0.03 μM against PGE2production. 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 IC50of 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.
Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology, Madras, Tamil Nadu, 600036, India.
Meera
M
Ramanan
Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology, Madras, Tamil Nadu, 600036, India.
Shweta
S
Sinha
Department of Chemistry, Indian Institute of Technology, Madras, Tamil Nadu, 600036, India.
Kasireddy
K
Sudarshan
Department of Chemistry, Indian Institute of Technology, Madras, Tamil Nadu, 600036, India. Electronic address: isingh@iitm.ac.in.
Indrapal Singh
IS
Aidhen
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.
Mukesh
M
Doble
D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D016718:Arachidonic Acid / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics; D015232:Dinoprostone / Q000096:biosynthesis; D005609:Free Radicals / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D049934:Isocoumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D015289:Leukotrienes / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011453:Prostaglandins / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; D005609:Free Radicals; D049934:Isocoumarins; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D011453:Prostaglandins; D012333:RNA, Messenger; D016718:Arachidonic Acid; D001094:Arachidonate 5-Lipoxygenase; D015232:Dinoprostone
5-Lipoxygenase; Inflammation; Isocoumarins; Microsomal prostaglandin E(2) synthase 1