Comparing Cyclophellitol N-Alkyl and N-Acyl Cyclophellitol Aziridines as Activity-Based Glycosidase Probes

The synthesis and evaluation as activity‐based probes (ABPs) of three configurationally distinct, fluorescent N‐alkyl cyclophellitol aziridine isosteres for profiling GH1 β‐glucosidase (GBA), GH27 α‐galactosidase (GLA) and GH29 α‐fucosidase (FUCA) is described. In comparison with the corresponding a...

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Bibliographic Details
Published in:Chemistry : a European journal 2015-07, Vol.21 (30), p.10861-10869
Main Authors: Jiang, Jianbing, Beenakker, Thomas J. M., Kallemeijn, Wouter W., van der Marel, Gijsbert A., van den Elst, Hans, Codée, Jeroen D. C., Aerts, Johannes M. F. G., Overkleeft, Herman S.
Format: Article
Language:English
Subjects:
activity-based protein profiling
alpha-Glucosidases - analysis
alpha-L-Fucosidase - analysis
Animals
aziridine
Aziridines - chemistry
beta-Glucosidase - analysis
biological activity
Cell Line
Cercopithecus aethiops
chemical biology
Chemistry
COS Cells
Cyclohexanols - chemistry
Electrophoresis, Polyacrylamide Gel
Fluorescence
Fluorescent Dyes - chemistry
Glycosidases
Handles
Marking
Media
Profiling
Synthesis
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Summary:The synthesis and evaluation as activity‐based probes (ABPs) of three configurationally distinct, fluorescent N‐alkyl cyclophellitol aziridine isosteres for profiling GH1 β‐glucosidase (GBA), GH27 α‐galactosidase (GLA) and GH29 α‐fucosidase (FUCA) is described. In comparison with the corresponding acyl aziridine ABPs reported previously, the alkyl aziridine ABPs are synthesized easily and are more stable in mild acidic and basic media, and are thus easier to handle. The β‐glucose‐configured alkyl aziridine ABP proves equally effective in labeling GBA as its N‐acyl counterpart, whereas the N‐acyl aziridines targeting GLA and FUCA outperform their N‐alkyl counterparts. Alkyl aziridines can therefore be an attractive alternative in retaining glycosidase ABP design, but in targeting a new retaining glycosidase both N‐alkyl and N‐acyl aziridines are best considered at the onset of a new study. Taking the challenge: Development of cyclophellitol alkyl aziridine activity‐based probes (ABPs) for labeling GH1 β‐glucosidase, GH27 α‐galactosidase and GH29 α‐fucosidase is described. These ABPs were compared with the corresponding acyl ABPs (see figure).
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.201501313