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

IF 1.5 4区 化学 Q3 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
{"title":"N-Methyl-N-Alkylaminocyclopentanes: Powerful and Selective β-d-Glucocerebrosidase Inhibitors","authors":"Patrick Weber,&nbsp;Roland Fischer,&nbsp;Seyed A. Nasseri,&nbsp;Bettina M. Pabst,&nbsp;Herwig Prasch,&nbsp;Arnold E. Stütz,&nbsp;Martin Thonhofer,&nbsp;Stephen G. Withers,&nbsp;Werner Windischhofer,&nbsp;Tanja M. Wrodnigg","doi":"10.1002/hlca.202300219","DOIUrl":null,"url":null,"abstract":"<p>Building upon a previously established (2+3)-cycloaddition strategy, a series of <i>N</i>,<i>N</i>-dialkylated aminocyclopentanes was synthesized using a partially protected eno-furanose as the starting point. The resulting <i>N</i>-methylisoxazolidine was subsequently transformed into the corresponding aminocyclopentane, which was further <i>N</i>-alkylated, yielding a collection of compounds with potential as inhibitors and pharmacological chaperones of β-<span>d</span>-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-<span>d</span>-glucocerebrosidase. However, none of these compounds exhibit significant activity enhancement of Morbus Gaucher related p.N409S/p.L483P mutant β-<span>d</span>-glucocerebrosidase.</p>","PeriodicalId":12842,"journal":{"name":"Helvetica Chimica Acta","volume":null,"pages":null},"PeriodicalIF":1.5000,"publicationDate":"2024-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Helvetica Chimica Acta","FirstCategoryId":"92","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/hlca.202300219","RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0

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。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Helvetica Chimica Acta
Helvetica Chimica Acta 化学-化学综合
CiteScore
3.00
自引率
0.00%
发文量
60
审稿时长
2.3 months
期刊介绍: Helvetica Chimica Acta, founded by the Swiss Chemical Society in 1917, is a monthly multidisciplinary journal dedicated to the dissemination of knowledge in all disciplines of chemistry (organic, inorganic, physical, technical, theoretical and analytical chemistry) as well as research at the interface with other sciences, where molecular aspects are key to the findings. Helvetica Chimica Acta is committed to the publication of original, high quality papers at the frontier of scientific research. All contributions will be peer reviewed with the highest possible standards and published within 3 months of receipt, with no restriction on the length of the papers and in full color.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信