ortho-Carborane-Modified N-Substituted Deoxynojirimycins

N‐alkyl‐deoxynojirimycins (DNMs) are an important class of glycoprocessing enzyme inhibitors. Our work on DNMs focuses on identifying potent and selective inhibitors of the human enzymes, glucosylceramide synthase (GCS), lysosomal glucosylceramidase (GBA) and neutral glucosylceramidase (GBA2). We ha...

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Bibliographic Details
Published in:European journal of organic chemistry 2015-07, Vol.2015 (20), p.4437-4446
Main Authors: Hoogendoorn, Sascha, Mock, Elliot D., Strijland, Anneke, Donker-Koopman, Wilma E., van den Elst, Hans, van den Berg, Richard J. B. H. N., Aerts, Johannes M. F. G., van der Marel, Gijsbert A., Overkleeft, Herman S.
Format: Article
Language:English
Subjects:
Carboranes
Enzymes
Glucosylceramide
Inhibitors
Medicinal chemistry
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Summary:N‐alkyl‐deoxynojirimycins (DNMs) are an important class of glycoprocessing enzyme inhibitors. Our work on DNMs focuses on identifying potent and selective inhibitors of the human enzymes, glucosylceramide synthase (GCS), lysosomal glucosylceramidase (GBA) and neutral glucosylceramidase (GBA2). We have previously reported on N‐alkylated DNM derivatives bearing various hydrophobic head groups (aliphatic, aromatic, branched, cyclic). In this study we report effective procedures for the synthesis of ortho‐carborane‐modified DNMs and establish the inhibitory potency of six new DNM derivatives 3–8 against GCS, GBA and GBA2. The synthesis of a series of ortho‐carborane‐containing deoxynojirimycin (DNM) derivatives is described. The resulting compounds are potent inhibitors of human glucosylceramidases and glucosylceramide synthase, with inhibitory profiles comparable to those of the corresponding adamantyl‐DNM derivatives.
ISSN:1434-193X
1099-0690
DOI:10.1002/ejoc.201500364