- Synthesis of sialyl Lewis(x) mimics: Replacement of galactose by aromatic spacers
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Six sLe(x) mimics where the galactose moiety is replaced by aromatic spacers have been prepared and tested for their binding affinity to E-selectin.
- Baenteli, Rolf,Ernst, Beat
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- Is adamantane a suitable substituent to pre-organize the acid orientation in E-selectin antagonists?
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The selectins play a key role in the inflammatory process, that is, the recruitment of leukocytes from blood vessels into inflamed tissue. Because excessive infiltration of leukocytes can induce acute or chronic reactions, the control of leukocyte extrava
- Titz, Alexander,Patton, John,Alker, Andre M.,Porro, Michele,Schwardt, Oliver,Hennig, Michael,Francotte, Eric,Magnani, John,Ernst, Beat
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p. 1046 - 1056
(2008/09/17)
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- Design and synthesis of E-selectin antagonists
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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.
- 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.
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p. 268 - 274
(2007/10/03)
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- Mimics of the sialyl Lewis X tetrasaccharide. Replacement of the N- acetylglucosamine sugar with simple C2-symmetric 1,2-diols
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Analogues of sialyl Lewis X have been synthesized that feature replacement of the N-acetylglucosamine residue with C2-symmetric diols. The diols used contain different levels of torsional constraint and various functional groups. The cyclohexyl derived compound 27 was equipotent to sLex in vitro (IC50 0.5 mM).
- Prodger,Bamford,Bird,Gore,Holmes,Priest,Saez
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p. 793 - 801
(2007/10/03)
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- Synthesis of novel mimetics of the sialyl Lewis X determinant
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Mimetics of the sialyl Lewis-X determinant in which at least one sugar domain is simulated by a di-, tri- or tetraalcohol unit have been synthesized. The inhibitory potency of these compounds for E- and P-selectin mediated cell adhesion has been evaluated in cell culture assays. The receptor binding affinity of the best of these mimetics was slightly higher than that of the natural oligosaccharide ligand sialyl Lewis X.
- Toepfer,Toepfer, Alexander,Kretzschmar,Kretzschmar, Gerhard,Bartnik,Bartnik, Eckart
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p. 9161 - 9164
(2007/10/02)
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