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Discovery of a novel enhydrazone ester (CEE‐1) that acts as a dual inhibitor of the release of pro‐inflammatory cytokines and prostanoids from human monocytes
Author(s) -
Ezeamuzie Charles,
Zamil Hanan,
AlBaghli Hawraa,
Edafiogho Ivan O
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb562
Subject(s) - prostanoid , chemistry , pharmacology , dexamethasone , in vitro , cytokine , tumor necrosis factor alpha , enzyme , proinflammatory cytokine , inflammation , biochemistry , prostaglandin , endocrinology , medicine
CEE‐1 (ethyl 4‐phenylhydrazinocyclohex‐3‐en‐2‐oxo‐6‐phenyl‐1‐oate) ‐ a novel enhydrazone ester, was synthesized and tested in vitro for anti‐inflammatory activity against the release of pro‐inflammatory cytokine and prostanoid from activated human monocytes. The effects were compared with those of standard anti‐inflammatory drugs dexamethasone and indomethacin. CEE‐1 potently and strongly inhibited the release of both TNF‐α and PGE 2 . The IC 50 values were 2.6 μM and 4.5 μM for TNF‐α and PGE 2 , respectively. At 30 μM, the drug achieved almost complete inhibition of both mediators. Dexamethasone had similar effects but indomethacin inhibited only the PGE 2 release, and although CEE‐1 was less potent than these two drugs, it had comparable efficacy. The compound appeared to act, at least, in part by inhibiting the up‐regulation of the mRNA for TNF‐α as well as that of the prostanoid‐synthetic enzyme, COX‐2. However, like dexamethasone, but unlike indomethacin, CEE‐1 did not affect COX‐2 enzyme function. Thus, CEE‐1 acts more like steroids rather than the non‐steroidal anti‐inflammatory drugs. Structure‐activity study showed that the presence of a simple aromatic ring attached via an NH‐NH group was critical for activity. At the concentrations that completely inhibited mediator release, the compound displayed no significant in vitro toxicity on the cells. These results show that CEE‐1 is a dual inhibitor of the release of cytokines and prostanoids, and therefore could be a potential alternative to steroids in the treatment of inflammatory diseases. This work was supported by Kuwait University, Research Sector grant # MR 03/09.