Institute of Molecular Pharmacy, University of Basel, CH-4056 Basel, Switzerland.
Bioorg Med Chem. 2010 Jan 1;18(1):19-27. doi: 10.1016/j.bmc.2009.11.024. Epub 2009 Nov 13.
The selectin-leukocyte interaction is the initial event in the early inflammatory cascade. This interplay proceeds via the terminal tetrasaccharide sialyl Lewis(x) (sLe(x)), present on physiological selectin ligands and E- and P-selectins located on the endothelial surface. Blocking this process is regarded as a promising therapeutic approach for inflammatory diseases where excessive leukocyte efflux is responsible for tissue damage. Selectin antagonists are generally based on sLe(x) as lead structure, containing the essential pharmacophores pre-oriented in the bioactive conformation. In this work, we describe a set of competitive sLe(x) mimetics possessing the carboxylic acid pharmacophore equipped with additional hydrophobic substituents as neuraminic acid (Neu5Ac) replacements. This small library of antagonists derived from Huisgen-1,3-dipolar cycloadditions allows to further probe the carbohydrate recognition domain of E-selectin.
选择素-白细胞相互作用是早期炎症级联反应的初始事件。这种相互作用通过生理选择素配体上存在的末端四糖唾液酸化路易斯（x）（sLe（x））和位于内皮表面的 E-选择素和 P-选择素进行。阻断这一过程被认为是一种有前途的治疗方法，适用于炎症性疾病，其中过度的白细胞外渗导致组织损伤。选择素拮抗剂通常以 sLe（x）为先导结构，包含预先定向在生物活性构象中的必需药效团。在这项工作中，我们描述了一组竞争性 sLe（x）类似物，它们具有羧酸药效团，并配备了额外的疏水性取代基作为神经氨酸（Neu5Ac）的替代品。这些源自 Huisgen-1,3-偶极环加成的拮抗剂文库可进一步探测 E-选择素的碳水化合物识别结构域。
