- Selection, synthesis, and anti-inflammatory evaluation of the arylidene malonate derivatives as TLR4 signaling inhibitors
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Inhibition of TLR4 signaling is an important therapeutic strategy for intervention in the etiology of several pro-inflammatory diseases. There has been intensive research in recent years aiming to explore this strategy, and identify small molecule inhibitors of the TLR4 pathway. However, the recent failure of a number of advanced drug candidates targeting TLR4 signaling (e.g., TAK242 and Eritoran) prompted us to continue the search for novel chemical scaffolds to inhibit this critical inflammatory response pathway. Here we report the identification of a group of new TLR4 signaling inhibitors through a cell-based screening. A series of arylidene malonate analogs were synthesized and assayed in murine macrophages for their inhibitory activity against LPS-induced nitric oxide (NO) production. The lead compound 1 (NCI126224) was found to suppress LPS-induced production of nuclear factor-kappaB (NF-κB), tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and nitric oxide (NO) in the nanomolar-low micromolar range. Taken together, this study demonstrates that 1 is a promising potential therapeutic candidate for various inflammatory diseases.
- Zhang, Shuting,Cheng, Kui,Wang, Xiaohui,Yin, Hang
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p. 6073 - 6079
(2012/11/07)
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- Synthesis of 5-alkylidene-1,3-dioxane-4,6-diones, an easily accessible family of axially chiral alkenes: Preparation in non-racemic form and platinum binding studies
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A general synthetic route to 5-alkylidene-1,3-dioxane-4,6-diones, which are a family of axially chiral alkenes, is described. Conformational issues are explored and the platinum-binding properties of these species are discussed. That these alkenes exist as stable enantiomers is established by their partial kinetic resolution upon reaction with cysteine. The Royal Society of Chemistry 2006.
- Casadesus, Meritxell,Coogan, Michael P.,Ooi, Li-Ling
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p. 3822 - 3830
(2008/09/18)
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- Competitive formation of β-amino acids, propenoic, and ylidenemalonic acids by the Rodionov reaction from malonic acid, aldehydes, and ammonium acetate in alcoholic medium
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The Rodionov reaction of 49 available aliphatic and aromatic aldehydes with malonic acid and ammonium acetate in alcoholic medium, resulting in formation of β-amino acids, propenoic, and ylidenemalonic acids, was studied. Certain regioselectivity regularities of the reaction were revealed. Among the variety of ketones studied, cyclohexanone is the only whose reaction yields a β-amino acid. Unusual dehydrofluorination of 6-chloro-2-fluorocinnamic acid under the Rodionov reaction was discovered. 2005 Pleiades Publishing, Inc.
- Lebedev,Lebedeva,Sheludyakov,Kovaleva,Ustinova,Kozhevnikov
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p. 1113 - 1124
(2007/10/03)
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- Mechanism of the one-pot synthesis of 3-amino-3-(2-nitrophenyl)propionic acid
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The one-pot synthesis of 3-amino-3-(2-nitrophenyl)propionic acid (1) from o-nitrobenzaldehyde, malonic acid in ammonium acetate/acetic acid occurs in 3 steps: condensation, addition and decarboxylation. Side reactions were investigated.
- Oelschlager,Ogorka,Kolbeck
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p. 488 - 492
(2007/10/02)
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