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

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.