Loading...
Synthesis and Evaluation of Eight- and Four-membered Iminosugar Analogues as Inhibitors of Testicular Ceramide-specific Glucosyltransferase, Testicular β-Glucosidase 2, and other Glycosidases
Lee, Jae Chul Francis, Subhashree Dutta, Dinah Gupta, Vijayalaxmi Yang, Yan Zhu, Jin-Yi Tash, Joseph S. Schönbrunn, Ernst Georg, Gunda I.
Lee, Jae Chul
Francis, Subhashree
Dutta, Dinah
Gupta, Vijayalaxmi
Yang, Yan
Zhu, Jin-Yi
Tash, Joseph S.
Schönbrunn, Ernst
Georg, Gunda I.
Citations
Altmetric:
Abstract
Eight- and four-membered analogues of N-butyldeoxynojirimycin (NB-DNJ), a reversible male contraceptive in mice, were prepared and tested. A chiral pool approach was used for the synthesis of the target compounds. Key steps for the synthesis of the eight-membered analogues involve: ringclosing metathesis and Sharpless asymmetric dihydroxylation, and for the four-membered analogues: Sharpless epoxidation, epoxide ring opening (azide), and Mitsunobu reaction to form the four-membered ring. (3S,4R,5S,6R,7R)-1-Nonylazocane-3,4,5,6,7-pentaol (6), was moderately active against rat-derived ceramide-specific glucosyltransferase and four of the other eight-membered analogues were weakly active against rat-derived β-glucosidase 2. Among the four-membered analogues, ((2R,3s,4S)-3-hydroxy-1-nonylazetidine-2,4-diyl)dimethanol (25), displayed selective inhibitory activity against mouse-derived ceramide-specific glucosyltransferase and was about half as potent as NB-DNJ against the rat-derived enzyme. ((2S,4S)-3-Hydroxy-1-nonyl-azetidine-2,4-diyl)dimethanol (27) was found to be a selective inhibitor of β-glucosidase 2, with potency similar to NB-DNJ. Additional glycosidase assays were performed to identify potential other therapeutic applications. The eight-membered iminosugars exhibited specificity for almond-derived β-glucosidase and the 1-nonylazetidine 25 inhibited α-glucosidase (Saccharomyces cerevisiae) with an IC50 of 600 nM and β-glucosidase (almond) with an IC50 of 20 µM. Only N-nonyl derivatives were active, emphasizing the importance of a long lipophilic side chain for inhibitory activity of the analogues studied.
Description
Date
2012-04-06
Journal Title
Journal ISSN
Volume Title
Publisher
American Chemical Society
Collections
Research Projects
Organizational Units
Journal Issue
Keywords
Citation
Lee, J. C., Francis, S., Dutta, D., Gupta, V., Yang, Y., Zhu, J.-Y., … Georg, G. I. (2012). Synthesis and Evaluation of Eight- and Four-membered Iminosugar Analogues as Inhibitors of Testicular Ceramide-specific Glucosyltransferase, Testicular β-Glucosidase 2, and other Glycosidases. The Journal of Organic Chemistry, 77(7), 3082–3098. http://doi.org/10.1021/jo202054g