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Design, Synthesis, and Biological Evaluation of New Peptide Analogues as Selective COX‐2 Inhibitors
Author(s) -
Ahmaditaba Mohammad A.,
Shahosseini Soraya,
Daraei Bahram,
Zarghi Afshin,
Houshdar Tehrani Mohammad H.
Publication year - 2017
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201700158
Subject(s) - chemistry , peptide , biological activity , cyclic peptide , combinatorial chemistry , stereochemistry , pharmacology , computational biology , biochemistry , biology , in vitro
A new class of peptide derivatives possessing SO 2 Me and N 3 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 50 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.