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Is adamantane a suitable substituent to pre-organize the acid orientation in E-selectin antagonists?

Titz, Alexander, Patton, John, Alker, Andre M, Porro, Michele, Schwardt, Oliver Roland, Hennig, Michael, Francotte, Eric, Magnani, John L. and Ernst, Beat (2008) Is adamantane a suitable substituent to pre-organize the acid orientation in E-selectin antagonists? Bioorganic & Medicinal Chemistry, 16 (2). pp. 1046-1056. ISSN 1464-3391


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 extravasation is of great pharmaceutical interest. All physiological ligands of the selectins contain the tetrasaccharide epitope sialyl Lewis(x), which therefore became the lead structure in selectin antagonist research. Previous studies indicated that an important factor for the affinity of sLe(x) is the fact that in solution its pharmacophores are already conformationally pre-organized in the bioactive orientation. In mimics where the GlcNAc- and the NeuNAc-moieties of sLe(x) were replaced by (R,R)-cyclohexane-1,2-diol and (S)-cyclohexyllactic acid, respectively, an optimized pre-organization of the pharmacophores could be realized, leading to antagonists with improved affinities. To further optimize the pre-organization of the carboxylic acid, a pharmacophore essential for binding, the replacement of NeuNAc by bulky (R)- and (S)-adamantyl-lactic acid was studied. Although antagonist (S)-7 showed a slightly reduced affinity, the expected beneficial effect of the (S)-configuration at C-2 of the lactate could be confirmed.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: E-selectin; Sialyl Lewisx; Pre-organization; Adamantane
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Date Deposited: 14 Dec 2009 13:50
Last Modified: 14 Dec 2009 13:50


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