Novel diarylheptanoids as inhibitors of TNF-α production

Synthesis and anti-inflammatory activity of novel diarylheptanoids [5-hydroxy-1-phenyl-7-(pyridin-3-yl)-heptan-3-ones and 1-phenyl-7-(pyridin-3-yl)hept-4-en-3-ones] as inhibitors of tumor necrosis factor-alpha (TNF-alpha) production is described in the present article. The key reactions involve the formation of a beta-hydroxyketone by the reaction of substituted 4-phenyl butan-2-ones with pyridine-3-carboxaldehyde in presence of LDA and the subsequent dehydration of the same to obtain the alpha,beta-unsaturated ketones. Compounds 4i, 5b, 5d, and 5g significantly inhibit lipopolysaccharide (LPS)-induced TNF-alpha production from human peripheral blood mononuclear cells in a dose-dependent manner. Of note, the in vitro TNF-alpha inhibition potential of 5b and 5d is comparable to that of curcumin (a naturally occurring diarylheptanoid). Most importantly, oral administration of 4i, 5b, 5d, and 5g (each at 100 mg/kg) but not curcumin (at 100 mg/kg) significantly inhibits LPS-induced TNF-alpha production in BALB/c mice. Collectively, our findings indicate that these compounds may have potential therapeutic implications for TNF-alpha-mediated auto-immune/inflammatory disorders. (C) 2011 Elsevier Ltd. All rights reserved.