Ortho‐Carborane‐Modified N‐Substituted Deoxynojirimycins. Issue 20 (9th June 2015)

• Record Type: Journal Article
• 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.
• Is Part Of: European journal of organic chemistry. Issue 20(2015)
• Page Start: 4437
• Page End: 4446
• Publication Date: 2015-06-09
• Subjects: Medicinal chemistry -- Enzymes -- Inhibitors -- Glucosylceramide -- Carboranes; Chemistry, Organic -- Periodicals; Organic compounds -- Synthesis -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1002/ejoc.201500364
• Languages: English
• ISSNs: 1434-193X

Abstract

Abstract: 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 derivatives3 –8 against GCS, GBA and GBA2. Abstract : 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.