New Glucocerebrosidase Inhibitors by Exploration of Chemical Diversity of N-Substituted Aminocyclitols Using Click Chemistry and in Situ Screening

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• 作者：Luci虂a Di虂az ; Josefina Casas ; Jordi Bujons ; Amadeu Llebaria ; Antonio Delgado
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：April 14, 2011
• 年：2011
• 卷：54
• 期：7
• 页码：2069-2079
• 全文大小：1055K
• 年卷期：v.54,no.7(April 14, 2011)
• ISSN：1520-4804

文摘

A library of aminocyclitols derived from CuAAC reaction between N-propargylaminocyclitol 4 and a series of azides [1鈭?b>25] is described and tested against GCase. Azides have been chosen from a large collection of potential candidates that has been filtered according to physical and reactivity constraints. A synthetic methodology has been optimized in order to avoid the use of protecting groups on the aminocyclitol scaffold. Because the reaction can be carried out in an aqueous system, the resulting library members can be screened in situ with minimal manipulation. From the preliminary GCase inhibition data, the most potent library members have been individually resynthesized for further biological screening and complete characterization. Some of the library members have shown biochemical data (IC₅₀, K_i, and stabilization ratio) similar or superior to those reported for NNDNJ. Docking studies have been used to postulate ligand鈭抏nzyme interactions to account for the experimental results.