N-Methyl-N-Alkylaminocyclopentanes: Powerful and Selective β-d-Glucocerebrosidase Inhibitors

IF 16.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Patrick Weber, Roland Fischer, Seyed A. Nasseri, Bettina M. Pabst, Herwig Prasch, Arnold E. Stütz, Martin Thonhofer, Stephen G. Withers, Werner Windischhofer, Tanja M. Wrodnigg
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Abstract

Building upon a previously established (2+3)-cycloaddition strategy, a series of N,N-dialkylated aminocyclopentanes was synthesized using a partially protected eno-furanose as the starting point. The resulting N-methylisoxazolidine was subsequently transformed into the corresponding aminocyclopentane, which was further N-alkylated, yielding a collection of compounds with potential as inhibitors and pharmacological chaperones of β-d-glucocerebrosidase. A comprehensive screening involving a range of biologically relevant glycosidases unveiled that these compounds exhibit remarkable potency and selectivity as inhibitors of human lysosomal β-d-glucocerebrosidase. However, none of these compounds exhibit significant activity enhancement of Morbus Gaucher related p.N409S/p.L483P mutant β-d-glucocerebrosidase.

Abstract Image

N-甲基-N-烷基氨基环戊烷:强效、选择性β-D-葡糖脑抑制剂
以先前建立的 (2+3)-cycloaddition 策略为基础,以部分保护的烯呋喃糖为起点,合成了一系列 N,N-二烷基化的氨基环戊烷。得到的 N-甲基异噁唑烷随后被转化为相应的氨基环戊烷,并对其进行进一步的 N-烷基化,从而得到了一系列具有作为 β-d- 葡糖脑苷脂抑制剂和药理合剂潜力的化合物。在对一系列生物相关糖苷酶进行全面筛选后发现,这些化合物作为人类溶酶体β-d-葡糖脑苷脂的抑制剂具有显著的效力和选择性。然而,这些化合物都不能显著增强与莫氏戈谢病相关的 p.N409S/p.L483P 突变体 β-d 葡糖脑的活性。
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来源期刊
Accounts of Chemical Research
Accounts of Chemical Research 化学-化学综合
CiteScore
31.40
自引率
1.10%
发文量
312
审稿时长
2 months
期刊介绍: Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.
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