293752-52-0Relevant articles and documents
Design and synthesis of E-selectin antagonists
Ernst, Beat,Dragic, Zorica,Marti, Sebastien,Mueller, Christian,Wagner, Beatrice,Jahnke, Wolfgang,Magnani, John L.,Norman, Keith E.,Oehrlein, Reinhold,Peters, Thomas,Kolb, Hartmuth C.
, p. 268 - 274 (2007/10/03)
Selectin-mediated recruitment of leukocytes plays a crucial role in a number of diseases and pathological situations, for example in inflammation, reperfusion injury, rheumatoid arthritis and respiratory diseases. Substantial research efforts are directed toward development of carbohydrate-derived drugs that interfere with the inflammatory response by blocking the selectin binding site. This article describes two approaches for the improvement of the inhibitory potency of the lead structure sialyl Lewisx (sLex). One approach is based on the preorganization of mimics in their bioactive conformation to reduce entropic costs. For the conformational analysis of mimics, molecular modeling based tools were developed. They allow the rational design of selectin antagonists with simplified structures, but increased inhibitory potency. Alternatively, additional carbohydrate/lectin contacts can be identified for the improvement of enthalpic contributions. Following this approach, an additional hydrophobic interaction of the antagonists with E-selectin leads to a 60-fold improvement of E-selectin affinity. Antagonists have been synthesized using chemical or chemo-enzymatic methods. Finally, a flow chart for the biological evaluation of the antagonists is presented.
Substrate specificity of fucosyl transferase III: An efficient synthesis of sialyl Lewis(x) -, sialyl Lewis(a)- derivatives and mimetics thereof
Ernst,Wagner,Baisch,Katopodis,Winkler,Ohrlein
, p. 892 - 904 (2007/10/03)
Fucosyl transferase III (FucT III) has previously been characterized as the most general enzyme of the FucT family, as judged from its ability to catalyze the transfer of fucose to both Galβ(1-3)GlcNAc and Galβ(1-4)GlcNAc. In order to explore the synthetic potential of FucT III for the enzymatic synthesis of sialyl Lewis(x) and sialyl Lewis(a) derivatives, its substrate specificity has been probed using a number of natural substrate mimetics. A remarkable range of acceptor substrates was found when N-acetyl glucosamine was replaced by D-glucal, (R,R)-1,2-cyclohexanediol and (R,R)-butan-2,3-diol. Although the reaction rates were low compared to the reaction with the natural substrates, they proved to be sufficient for the synthesis of preparative amounts.
