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

• Published in: New journal of chemistry Vol. 43; no. 2; p. 834
• Main Authors: Puratchikody, Ayarivan, Appavoo Umamaheswari, Navabshan Irfan, Sinha, Shweta, Manju, S L, Ramanan, Meera, Ramamoorthy, Gayathri, Doble, Mukesh
• Format: Journal Article
• Language: English
• Published: Cambridge Royal Society of Chemistry 01.01.2019
• Subjects: Anticancer properties; Cancer; Cell cycle; Chlorine; COX-2 inhibitors; Derivatives; Disruption; Gene expression; Inflammation; Iodine; Liquid oxygen; Medical research; Tyrosine
• ISSN: 1144-0546; 1369-9261
• DOI: 10.1039/c8nj04385j

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.