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Synthesis and Evaluation of Eight- and Four-membered Iminosugar Analogues as Inhibitors of Testicular Ceramide-specific Glucosyltransferase, Testicular β-Glucosidase 2, and other Glycosidases
dc.contributor.author | Lee, Jae Chul | |
dc.contributor.author | Francis, Subhashree | |
dc.contributor.author | Dutta, Dinah | |
dc.contributor.author | Gupta, Vijayalaxmi | |
dc.contributor.author | Yang, Yan | |
dc.contributor.author | Zhu, Jin-Yi | |
dc.contributor.author | Tash, Joseph S. | |
dc.contributor.author | Schönbrunn, Ernst | |
dc.contributor.author | Georg, Gunda I. | |
dc.date.accessioned | 2017-04-13T15:31:31Z | |
dc.date.available | 2017-04-13T15:31:31Z | |
dc.date.issued | 2012-04-06 | |
dc.identifier.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 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/23678 | |
dc.description.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. | en_US |
dc.publisher | American Chemical Society | en_US |
dc.rights | This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Organic Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jo202054g. | en_US |
dc.title | Synthesis and Evaluation of Eight- and Four-membered Iminosugar Analogues as Inhibitors of Testicular Ceramide-specific Glucosyltransferase, Testicular β-Glucosidase 2, and other Glycosidases | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Dutta, Dinah | |
kusw.kudepartment | Medicinal Chemistry | en_US |
dc.identifier.doi | 10.1021/jo202054g | en_US |
kusw.oaversion | Scholarly/refereed, author accepted manuscript | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.rights.accessrights | openAccess |