Li Huang-Yi, Chen Wei-An, Lin Hung-Yi, Tsai Chi-Wei, Chiu Yu-Ting, Yun Wen-Yi, Lee Ni-Chung, Chien Yin-Hsiu, Hwu Wuh-Liang, Cheng Wei-Chieh
Genomics Research Center, Academia Sinica, 128, Section 2, Academia Road, Taipei, 11529, Taiwan.
Department of Pediatrics and Medical Genetics, National Taiwan University Hospital, 8 Chung-Shan South Road, Taipei, 10041, Taiwan.
Commun Chem. 2024 Apr 20;7(1):91. doi: 10.1038/s42004-024-01164-9.
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.
异麦角胺（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。在此，我们展示了一种通过氰化物向环状硝酮1的非对映选择性加成来实际合成基于C5a-S和R氨甲基IFG的衍生物的方法。硝酮1可通过一种直接的方法从廉价的（-）-二乙基D-酒石酸方便地以克级规模高产率制备，其中硝基烯烃的立体选择性迈克尔加成和涅夫反应为关键步骤。一个由268个成员（134×2）组成的C5a功能化衍生物文库接受了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，在25 nM时，其在p.Asn370Ser GCase活性方面提高了2.7倍，在1 μM时，在高雪氏细胞系中重组人GCase活性提高了13倍。
