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A novel class of tyrosine derivatives as dual 5-LOX and COX-2/mPGES1 inhibitors with PGE2 mediated anticancer properties

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Abstract

Leukotriene and prostaglandin pathways are controlled by the enzymes, LOX and COX/mPGES1 respectively and are responsible for inflammatory responses. PGE2, produced by mPGES1, leads to the progression of inflammation as well as cancer. A series of 19 novel tyrosine derivatives are synthesized, characterized and tested against 5-LOX, in vitro, and production of PGE2, in HeLa cells. 6b-v and 6c-i, are found to possess maximum inhibitory action against 5-LOX and PGE2 production. The compound 6b-v is found to act by disrupting the redox cycle of the 5-LOX enzyme, and its activity is comparable to that of the commercial drug, Zileuton. The activity of the other compound 6c-i is comparable to a drug in clinical trials, Licofelone, and it has been found to inhibit the mRNA expression of mPGES1 predominantly. It also arrests the HeLa cells in the S and G2/M phases of the cell cycle indicating anticancer activity. Also, compounds, 6b-iv and 6b-viii inhibit both the LT & PG pathways in the inflammation cascade. Presence of iodine in the phenyl ring appears to favour the inhibition of 5-LOX whereas chlorine favours the inhibition of PGE2 production. These leads could be further optimized and developed as drugs against inflammation and cancer.

Graphical abstract: A novel class of tyrosine derivatives as dual 5-LOX and COX-2/mPGES1 inhibitors with PGE2 mediated anticancer properties

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Publication details

The article was received on 28 Aug 2018, accepted on 03 Dec 2018 and first published on 04 Dec 2018


Article type: Paper
DOI: 10.1039/C8NJ04385J
Citation: New J. Chem., 2019, Advance Article
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    A novel class of tyrosine derivatives as dual 5-LOX and COX-2/mPGES1 inhibitors with PGE2 mediated anticancer properties

    A. Puratchikody, A. Umamaheswari, N. Irfan, S. Sinha, S. L. Manju, M. Ramanan, G. Ramamoorthy and M. Doble, New J. Chem., 2019, Advance Article , DOI: 10.1039/C8NJ04385J

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