CD22, one of the sialic acid-binding immunoglobulin-like lectins (Siglecs), regulates B lymphocyte signaling via its interaction with glycan ligands bearing the sequence Neu5Ac/Gcα(2→6)Gal. We have developed the synthetic sialoside GSC-718 as a ligand mimic for CD22 and identified it as a potent CD22 inhibitor. Although the synthesis of CD22-binding sialosides including GSC-718 has been reported by our group, the synthetic route was unfortunately not suitable for large-scale synthesis. In this study, we developed an improved scalable synthetic procedure for sialosides which utilized 1,5-lactam formation as a key step. The improved procedure yielded sialosides incorporating a series of aglycones at the C2 position. Several derivatives with substituted benzyl residues as aglycones were found to bind to mouse CD22 with affinity comparable to that of GSC-718. The new procedure developed in this study affords sialosides in sufficient quantities for cell-based assays, and will facilitate the search for promising CD22 inhibitors that have therapeutic potential.

CD22 是一种唾液酸结合免疫球蛋白样凝集素 (Siglecs)，它通过与序列为 Neu5Ac/Gcα(2→6)Gal 的聚糖配体相互作用来调节 B 淋巴细胞信号传导。我们开发了合成唾液酸苷 GSC-718 作为 CD22 的配体模拟物，并将其鉴定为有效的 CD22 抑制剂。虽然我们小组已经报道了包括 GSC-718 在内的 CD22 结合唾液酸苷的合成，但遗憾的是合成路线不适合大规模合成。在这项研究中，我们开发了一种改进的可扩展的唾液酸苷合成程序，该程序利用 1,5-内酰胺形成作为关键步骤。改进的程序产生了在 C2 位置包含一系列糖苷配基的唾液酸苷。发现几种具有取代的苄基残基作为糖苷配基的衍生物以与 GSC-718 相当的亲和力与小鼠 CD22 结合。本研究开发的新程序为基于细胞的测定提供了足够数量的唾液酸苷，并将有助于寻找具有治疗潜力的有前途的 CD22 抑制剂。