Design, Synthesis, and Biological Evaluation of New Peptide Analogues as Selective COX‐2 Inhibitors

Abstract

A new class of peptide derivatives possessing SO Me and N pharmacophores at the para position of a phenyl ring bound to different aromatic amino acids were synthesized based on solid-phase synthesis methodology, and evaluated as selective cyclooxygenase-2 (COX-2) inhibitors. One of the analogues, i.e., compound 2a as the representative of this series, was recognized as the highest selective COX-2 inhibitor with a COX-2 selectivity index of >500. The structure-activity relationships (SARs) acquired indicated that compound 2a containing a 4-(methylsulfonyl)benzoyl group as a pharmacophore and tyrosine as a ring bearing amino acid in the second position and glutamic acid as the C-terminal amino acid can give the essential geometry to provide selective COX-2 inhibitory activity. Antiproliferative activity of the synthesized peptides (1a-7b) was also determined against four different human cancer cell lines, including MCF-7, HepG2, A549, and HeLa. According to our results, A549, HepG2, and MCF7 seemed to be more sensitive cell lines than HeLa cells encountering these compounds, which gave inhibitory action with IC values from 4.8 to 64.4 µM. In this regard, compounds 3a and 2b displayed the best inhibitory activity against the cell lines. Moreover, a good correlation was observed between the antiproliferative potency and the COX-2 inhibitory activity of compounds 1a, 2a, 2b, and 5b. Such findings suggest that one of the mechanism of anticancer activity of these peptides may be through the COX-2 inhibitory action.

Anticancer peptide: Physicochemical property, functional aspect and trend in clinical application (Review)

“…Tyrosine and tryptophan are weakly hydrophobic amino acids; tyrosine does not serve a role in toxicity of ACPs, whereas tryptophan may exert a role in the toxicity of some ACPs against cancer cells such as indolicidin and trans-activator of transportation (TAT)-Ras GTPase-activating protein-326 peptides (19,58,59). However, synthesized peptides containing tryptophan and histidine may decrease cytotoxicity, while those containing tyrosine, phenylalanine or proline may be able to increase cytotoxic activity (60). The tryptophan position on the cell-penetrating peptides serves an important role in entering cancer cells, which subsequently involves an endocytic pathway and binding at the major groove of nuclear DNA (61).…”

Mechanisms of Phytonutrient Modulation of Cyclooxygenase-2 (COX-2) and Inflammation Related to Cancer

“…Recently a new class of peptide derivatives was recognized as the highest selective COX-2 inhibitor with a COX-2 selectivity index of >500 (80). Ultimately, these drugs had a high risk of producing thrombotic cardiovascular events, and showed little improvement in preventing gastrointestinal ulcers (81).…”

Peptides with Dual Antimicrobial–Anticancer Activity: Strategies to Overcome Peptide Limitations and Rational Design of Anticancer Peptides

“…Negatively charged amino acids, such as aspartic acid and glutamic acid have antiproliferative activity on tumor cells [ 103 ]. Proline, tyrosine, and phenylalanine are characterized by their interaction with the phospholipids of the cancer cell membrane and increase the cytotoxicity of anticancer peptide [ 81 , 104 , 105 ]. It has also been observed that proline insertion tends to reduce helicity, similarly to D-amino acids, leading to reduced activity [ 63 ].…”