Synthesis and glycosidase inhibition of 3,4,5-trihydroxypiperidines using a one-pot amination-cyclisation cascade reaction

IF 2.4 3区 化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Emma M. Dangerfield , Michael A. Meijlink , Alex A. Hunt-Painter , Seyed A. Nasseri , Stephen G. Withers , Bridget L. Stocker , Mattie S.M. Timmer
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Abstract

Trihydroxypiperidines are a therapeutically valuable class of iminosugar. We applied a one-pot amination-cyclisation cascade reaction to synthesise 3,4,5-trihydroxypiperidine stereoisomers in three steps from commercially available pentoses and in excellent overall yields. Using our methodology, the yields of the syntheses of meso-1, meso-2 and 3L are the highest reported to date. The synthetic methodology was readily extended to the three-step synthesis of N-alkyl derivatives by replacing the ammonia nitrogen source with a primary amine. The trihydroxypiperidines and N-alkyl analogues were screened for enzyme inhibitory activity using Fabrazyme (Fabry disease), GCase (Gaucher's disease), Agrobacterium sp. β-glucosidase, and Escherichia coli β-galactosidase. N-Phenylethyl 3,4,5-trihydroxypiperidine (N-phenylethyl-1-(3R,4R,5S)-piperidine-3,4,5-triol) showed good inhibitory activity of Fabrazyme (Ki = 46 μM). This activity was abolished when the N-phenylethyl group was removed or replaced with a non-aromatic alkyl chain.

Abstract Image

利用单锅氨基化-环化级联反应合成 3,4,5-三羟基哌啶并抑制糖苷酶。
三羟基哌啶是一类具有治疗价值的亚氨基糖。我们采用一锅胺化-环化级联反应,从市售的戊糖出发,分三步合成了 3,4,5-三羟基哌啶立体异构体,而且总收率极高。使用我们的方法合成介-1、介-2 和 3L 的收率是迄今为止所报道的最高的。通过用伯胺代替氨氮源,合成方法很容易扩展到三步合成 N-烷基衍生物。利用法布雷酶(法布雷病)、GCase(戈谢病)、农杆菌β-葡萄糖苷酶和大肠杆菌β-半乳糖苷酶对三羟基哌啶和 N-烷基类似物的酶抑制活性进行了筛选。N- 苯乙基 3,4,5-三羟基哌啶(N-苯乙基-1-(3R,4R,5S)-哌啶-3,4,5-三醇)对法布拉酶具有良好的抑制活性(Ki = 46 μM)。当 N-苯基乙基被移除或被非芳香族烷基链取代时,这种活性就会消失。
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来源期刊
Carbohydrate Research
Carbohydrate Research 化学-生化与分子生物学
CiteScore
5.00
自引率
3.20%
发文量
183
审稿时长
3.6 weeks
期刊介绍: Carbohydrate Research publishes reports of original research in the following areas of carbohydrate science: action of enzymes, analytical chemistry, biochemistry (biosynthesis, degradation, structural and functional biochemistry, conformation, molecular recognition, enzyme mechanisms, carbohydrate-processing enzymes, including glycosidases and glycosyltransferases), chemical synthesis, isolation of natural products, physicochemical studies, reactions and their mechanisms, the study of structures and stereochemistry, and technological aspects. Papers on polysaccharides should have a "molecular" component; that is a paper on new or modified polysaccharides should include structural information and characterization in addition to the usual studies of rheological properties and the like. A paper on a new, naturally occurring polysaccharide should include structural information, defining monosaccharide components and linkage sequence. Papers devoted wholly or partly to X-ray crystallographic studies, or to computational aspects (molecular mechanics or molecular orbital calculations, simulations via molecular dynamics), will be considered if they meet certain criteria. For computational papers the requirements are that the methods used be specified in sufficient detail to permit replication of the results, and that the conclusions be shown to have relevance to experimental observations - the authors'' own data or data from the literature. Specific directions for the presentation of X-ray data are given below under Results and "discussion".
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