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A practical synthesis of nitrone-derived C5a-functionalized isofagomines as protein stabilizers to treat Gaucher disease
Communications Chemistry ( IF 5.9 ) Pub Date : 2024-04-20 , DOI: 10.1038/s42004-024-01164-9
Huang-Yi Li , Wei-An Chen , Hung-Yi Lin , Chi-Wei Tsai , Yu-Ting Chiu , Wen-Yi Yun , Ni-Chung Lee , Yin-Hsiu Chien , Wuh-Liang Hwu , Wei-Chieh Cheng

Isofagomine (IFG) and its analogues possess promising glycosidase inhibitory activities. However, a flexible synthetic strategy toward both C5a-functionalized IFGs remains to be explored. Here we show a practical synthesis of C5a-S and R aminomethyl IFG-based derivatives via the diastereoselective addition of cyanide to cyclic nitrone 1. Nitrone 1 was conveniently prepared on a gram scale and in high yield from inexpensive (−)-diethyl d-tartrate via a straightforward method, with a stereoselective Michael addition of a nitroolefin and a Nef reaction as key steps. A 268-membered library (134 × 2) of the C5a-functionalized derivatives was submitted to enzyme- or cell-based bio-evaluations, which resulted in the identification of a promising β-glucocerebrosidase (GCase) stabilizer demonstrating a 2.7-fold enhancement at 25 nM in p.Asn370Ser GCase activity and a 13-fold increase at 1 μM in recombinant human GCase activity in Gaucher cell lines.



中文翻译:


硝酮衍生的 C5a 功能化异法戈明作为蛋白质稳定剂治疗戈谢病的实用合成



异法戈明 (IFG) 及其类似物具有良好的糖苷酶抑制活性。然而,针对 C5a 功能化 IFG 的灵活合成策略仍有待探索。在这里,我们展示了通过将氰化物非对映选择性加成到环状硝酮1上来实际合成 C5a- SR氨甲基 IFG 衍生物。硝基酮1可以通过简单的方法,以硝基烯烃的立体选择性迈克尔加成和 Nef 反应为关键步骤,以廉价的 (-)- d-酒石酸二乙酯为原料,以克级的方式以高产率方便地制备。将 C5a 功能化衍生物的 268 成员文库 (134 × 2) 提交给基于酶或细胞的生物评估,结果鉴定出一种有前景的 β-葡萄糖脑苷脂酶 (GCase) 稳定剂,其性能增强了 2.7 倍在戈谢细胞系中,p.Asn370Ser GCase 活性在 25 nM 时增加,1 μM 时重组人 GCase 活性增加 13 倍。

更新日期:2024-04-21
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