The ethyl pyruvate analogues, diethyl oxaloproprionate, 2-acetamidoacrylate, and methyl-2-acetamidoacrylate, exhibit anti-inflammatory properties in vivo and/or in vitro.
Ethyl pyruvate (EP) is a simple aliphatic ester derived from the endogenous metabolite, pyruvic acid. EP has been shown to decrease the expression of various pro-inflammatory mediators, including nitric oxide (NO*), tumor necrosis factor (TNF), cyclooxygenase-2, and interleukin (IL)-6, in a variety of in vitro and in vivo model systems. In an effort to better understand the chemical features that might explain the anti-inflammatory properties of EP, we screened 15 commercially available compounds for cytoprotective or anti-inflammatory effects using two in vitro assay systems: TNF and NO* production by lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophage-like cells and changes in the permeability of Caco-2 human enterocyte-like monolayers stimulated with a cocktail of pro-inflammatory cytokines called cytomix (1000U/ml IFN-gamma plus 10ng/ml TNF-alpha plus 1ng/ml IL-1beta). Two compounds, namely diethyl oxaloproprionate (DEOP) and 2-acetamidoacrylate (2AA), demonstrated consistent anti-inflammatory or cytoprotective pharmacological properties in this screening process. Treatment of mice with either of these compounds ameliorated LPS-induced ileal mucosal hyperpermeability to the fluorescent probe, fluorescein isothiocyanate-labeled dextran (average molecular mass 4kDa), and bacterial translocation to mesenteric lymph nodes. Treatment with either of these compounds also improved survival in mice challenged with a lethal dose of LPS. Finally, in a study that compared 2AA to its methyl ester, we showed that methyl-2-acetamidoacrylate is at least 100-fold more potent than the parent carboxylate as an inhibitor of LPS-induced NO* production by RAW 264.7 cells. Collectively, these data are consistent with the view that anti-inflammatory activity is demonstrable for a number of compounds that either incorporate an olefinic linkage conjugated to a carbonyl moiety or are capable of undergoing tautomeric rearrangement to form such a structure. Moreover, our findings suggest that esters with these general characteristics, perhaps because of their greater lipophilicity or electrophilicity, are more potent anti-inflammatory agents than are the parent carboxylates.
Sappington
Penny L
PL
Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 616 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA.
Cruz
Ruy J
RJ
Harada
Tomoyuki
T
Yang
Runkuan
R
Han
Yusheng
Y
Englert
Joshua A
JA
Ajami
Alfred A
AA
Killeen
Meaghan E
ME
Delude
Russell L
RL
Fink
Mitchell P
MP
D000179:Acrylates / Q000737:chemistry / Q000494:pharmacology*; D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D004952:Esters / Q000737:chemistry / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D015227:Lipid Peroxidation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D011422:Propionates; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000179:Acrylates; D000893:Anti-Inflammatory Agents; D004952:Esters; D008070:Lipopolysaccharides; C457541:N-acetyldehydroalanine; D016328:NF-kappa B; D011422:Propionates; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C011392:N-acetyldehydroalanine methyl ester; C506271:diethyl oxalopropionate; D005978:Glutathione; D000409:Alanine