A concise asymmetric synthesis of clickable enantiomeric pyrrolidines was achieved using Crabbé-Ma allenation. The synthesized iminosugars were grafted by copper–free strain-promoted alkyne-azide cycloaddition onto phosphorus dendrimers. The hexavalent and dodecavalent pyrrolidines were evaluated as β–glucocerebrosidase inhibitors. The level of inhibition suggests that monofluorocyclooctatriazole group may contribute to the affinity for the protein leading to potent multivalent inhibitors. Docking studies were carried out to rationalize these results. Then, the iminosugars clusters were evaluated as pharmacological chaperones in Gaucher patients’ fibroblasts. An increase in β–glucocerebrosidase activity was observed with hexavalent and dodecavalent pyrrolidines at concentrations as low as 1 µM and 0.1 µM, respectively. These iminosugar clusters constitute the first example of multivalent pyrrolidines acting as pharmacological chaperones against Gaucher disease.

中文翻译：

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多价吡咯烷作为抗戈谢病的药理学伴侣

使用 Crabbé-Ma 异化反应实现了可点击对映体吡咯烷的简明不对称合成。通过无铜应变促进的炔叠氮环加成将合成的亚氨基糖接枝到磷树枝状聚合物上。六价和十二价吡咯烷被评估为β-葡萄糖脑苷脂酶抑制剂。抑制水平表明单氟环八三唑基团可能有助于蛋白质的亲和力，从而产生有效的多价抑制剂。进行对接研究以使这些结果合理化。然后，评估亚氨基糖簇作为戈谢病患者成纤维细胞中药理学伴侣的作用。当六价和十二价吡咯烷浓度分别低至 1 µM 和 0.1 µM 时，观察到 β-葡萄糖脑苷脂酶活性增加。这些亚氨基糖簇构成了多价吡咯烷作为对抗戈谢病的药理学伴侣的第一个例子。