Design, Synthesis, and Evaluation of New Tripeptides as COX-2 Inhibitors

Abstract

Cyclooxygenase (COX) is a key enzyme in the biosynthetic pathway leading to the formation of prostaglandins, which are mediators of inflammation. It exists mainly in two isoforms COX-1 and COX-2. The conventional nonsteroidal anti-inflammatory drugs (NSAIDs) have gastrointestinal side effects because they inhibit both isoforms. Recent data demonstrate that the overexpression of these enzymes, and in particular of cyclooxygenases-2, promotes multiple events involved in tumorigenesis; in addition, numerous studies show that the inhibition of cyclooxygenases-2 can delay or prevent certain forms of cancer. Agents that inhibit COX-2 while sparing COX-1 represent a new attractive therapeutic development and offer a new perspective for a further use of COX-2 inhibitors. The present study extends the evaluation of the COX activity to all 203 possible natural tripeptide sequences following a rational approach consisting in molecular modeling, synthesis, and biological tests. Based on data obtained from virtual screening, only those peptides with better profile of affinity have been selected and classified into two groups called S and E. Our results suggest that these novel compounds may have potential as structural templates for the design and subsequent development of the new selective COX-2 inhibitors drugs.

Structure–activity relationships for the synthesis of selective cyclooxygenase 2 inhibitors: an overview (2009–2016)

“…This natural compound was the subject of several chemical modifications aimed at creat-ing semisynthetic derivatives 50 and α-amino acids, which were docked, as new tripeptides, in the COX-2 active site to ensure inhibition. 51 Hydrocinnamic acid has been used to design a series of various ether and ester derivatives acting as COX-2 inhibitors, with a good result for caffeic acid diethyl ester (CA-DE), which forms 3 hydrogen bonds with the active site of COX-2 (4-OH⋯OH-Tyr355, 4-OH⋯NH-Arg120 and CO⋯OH-Tyr385). 52 In addition, other small peptides have been designed to improve the potent anti-inflammatory action via COX-2 inhibition; specifically, H 2 N-Gly-Gly-Phe-Leu-OMe with an IC 50 value of 0.06 μM demonstrates good selective COX-2 inhibition and good anti-inflammatory activity.…”

Alleviating Promotion of Inflammation and Cancer Induced by Nonsteroidal Anti-Inflammatory Drugs

“…The most evident difference between COX isoenzymes is in their expression in tissue distribution. Unlike COX-1, which is ubiquitous and constitutively expressed throughout the gastrointestinal system, the kidneys, the vascular smooth muscle, and the platelets, COX-2 is constitutively expressed in endothelial cells, brain, and kidneys and is variably induced in its expression by distinct inflammatory stimuli and neoplastic conditions [ 15 , 16 ]. Unexplained antipyretic and analgesic effects of acetaminophen, phenacetin, and dipyrone, without evident COX-1 or COX-2 inhibition, were made clear by the discovery of yet another COX isoenzyme termed COX-3 that when expressed showed selective inhibition to these agents [ 17 ].…”