85985-64-4Relevant articles and documents
Structural and functional characterization of pronyl-lysine, a novel protein modification in bread crust melanoidins showing in vitro antioxidative and phase I/II enzyme modulating activity
Lindenmeier, Michael,Faist, Veronika,Hofmann, Thomas
, p. 6997 - 7006 (2002)
Application of an in vitro antioxidant assay to solvent fractions isolated from bread crust, bread crumb, and flour, respectively, revealed the highest antioxidative potential for the dark brown, ethanol solubles of the crust, whereas corresponding crumb and flour fractions showed only minor activities. To investigate whether these browning products may also act as antioxidants in biological systems, their modulating activity on detoxification enzymes was investigated as a functional parameter in intestinal Caco-2 cells. The bread crust and, in particular, the intensely brown, ethanolic crust fraction induced a significantly elevated glutathione S-transferase (GST) activity and a decreased phase I NADPH-cytochrome c reductase (CCR) activity compared to crumb-exposed cells. Antioxidant screening of Maillard-type model mixtures, followed by structure determination, revealed the pyrrolinone reductones 1 and 2 as the key antioxidants formed from the hexose-derived acetylformoin and Nα-acetyl-L-lysine methyl ester or glycine methyl ester, chosen as model substances to mimic nonenzymatic browning reactions with the lysine side chain or the N terminus of proteins, respectively. Quantitation of protein-bound pyrrolinone reductonyl-lysine, abbreviated pronyl-lysine, revealed high amounts in the bread crust (62.2 mg/kg), low amounts in the crumb (8.0 mg/kg), and the absence of this compound in untreated flour. Exposing Caco-2 cells for 48 h to either synthetically pronylated albumin or purified pronyl-glycine (3) significantly increased phase II GST activity by 12 or 34%, respectively, thus demonstrating for the first time that "pronylated" proteins as part of bread crust melanoidins act as monofunctional inducers of GST, serving as a functional parameter of an antioxidant, chemopreventive activity in vitro.
Maximizing lipophilic efficiency: The use of Free-Wilson analysis in the design of inhibitors of acetyl-CoA carboxylase
Freeman-Cook, Kevin D.,Amor, Paul,Bader, Scott,Buzon, Leanne M.,Coffey, Steven B.,Corbett, Jeffrey W.,Dirico, Kenneth J.,Doran, Shawn D.,Elliott, Richard L.,Esler, William,Guzman-Perez, Angel,Henegar, Kevin E.,Houser, Janet A.,Jones, Christopher S.,Limberakis, Chris,Loomis, Katherine,McPherson, Kirk,Murdande, Sharad,Nelson, Kendra L.,Phillion, Dennis,Pierce, Betsy S.,Song, Wei,Sugarman, Eliot,Tapley, Susan,Tu, Meihua,Zhao, Zhengrong
supporting information; experimental part, p. 935 - 942 (2012/03/11)
This paper describes the design and synthesis of a novel series of dual inhibitors of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2). Key findings include the discovery of an initial lead that was modestly potent and subsequent medicinal chemistry optimization with a focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided a clear breakdown of the contributions of specific structural elements to the overall LipE, a rationale for prioritization of virtual compounds for synthesis, and a highly successful prediction of the LipE of the resulting analogues. Further preclinical assays, including in vivo malonyl-CoA reduction in both rat liver (ACC1) and rat muscle (ACC2), identified an advanced analogue that progressed to regulatory toxicity studies.
Reactions of Glyoxals with Hydrazones: A New Route to 4-Hydroxypyrazoles
Begtrup, Mikael,Nytoft, Hans Peter
, p. 81 - 86 (2007/10/02)
N-Substituated hyrazones of aldehydes react with glyoxals under non-aqueous conditions to give N-substituted 4-hydroxypyrazoles; fourteen such products are described.In the presence of water, N-substituted 3-acyl-4-hydroxypyrazoles are produced from 2-oxoaldehyde hydrazones and glyoxals.It is shown that glyoxals combine in a 1:1 ratio with N-monosubstituted hydrazones to give 2-hydrazonoaldehydes as the kinetically controlled products.At room temperature or lower, these hydrazonoaldehydes rearrange to the more stable 2-oxoaldehyde hydrazones and react with glyoxals to give N-substituted 3-acyl-4-hydroxypyrazoles; sixteen such products are described.This synthesis, involving easily accessible starting materials, opens up a new, and for certain derivatives exclusive, route to 4-hydroxypyrazoles.
