Î±-GLUCOSIDASE INHIBITION OF LACTONE INTERMEDIATES OF THE IMINOSUGAR DEOXYNOJIRIMYCIN

Yong Wai Haan; Hussein M. Al-Bajalan; Edison Eukun Sage; Dharshini Elangovan; Noor Liana Mat Yajit; Nur Maisarah Sarizan; Nicole Zitzmann; J. L. Kiappes; Siti Aishah Hasbullah; Nor Hadiani Ismail; Mukram Mohamed Mackeen

doi:10.11113/jt.v81.13079

Authors

Yong Wai Haan
Hussein M. Al-Bajalan
Edison Eukun Sage Chemistry Programme, Centre for Advanced Materials and Renewable Resources, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia
Dharshini Elangovan Chemistry Programme, Centre for Advanced Materials and Renewable Resources, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia
Noor Liana Mat Yajit Centre for Biotechnology and Functional Food, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia
Nur Maisarah Sarizan Institute of Systems Biology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia
Nicole Zitzmann Oxford Glycobiology Institute, University of Oxford, Oxford OX1 3QU, United Kingdom
J. L. Kiappes Oxford Glycobiology Institute, University of Oxford, Oxford OX1 3QU, United Kingdom
Siti Aishah Hasbullah Chemistry Programme, Centre for Advanced Materials and Renewable Resources, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia
Nor Hadiani Ismail Atta-ur-Rahman Institute for Natural Products Discovery, Universiti Teknologi MARA, Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor, Malaysia
Mukram Mohamed Mackeen Chemistry Programme, Centre for Advanced Materials and Renewable Resources, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia Institute of Systems Biology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia

DOI:

https://doi.org/10.11113/jt.v81.13079

Keywords:

D-Glucuronolactone (1), 1, 2-O-isopropylidene-Î±-D-glucurono-3, 6-lactone (2), 2-O-isopropylidene-Î²-L-idurono-3, 6-lactone (3), 5-azido-5-deoxy-1, 6-lactone (4), iminosugar, deoxynojirimycin, Î±-glucosidase inhibition

Abstract

Î±-Glycosidase enzymes hydrolyse Î±-glycosidic linkages and are involved in bodily processes such as the catabolism of glycans, intestinal digestion, and the degradation of glycoproteins. Various types of diseases which are caused by the failure of this enzyme to function properly can be treated through enzyme inhibition. The hydroxyethyl derivative of DNJ (Miglitol) is a clinical drug for the treatment of type 2 diabetes. Although the iminosugar D-deoxynojirimisin (D-DNJ) is an excellent micromolar glycosidase inhibitor, the Î±-glucosidase inhibition activity of D-DNJ lactone intermediates has yet to be reported. Therefore, the scalable synthesis of the D-DNJ intermediates 1,2-O-isopropylidene-Î±-D-glucurono-3,6-lactone (2), 1,2-O-isopropylidene-Î²-L-idurono-3,6-lactone (3) and 5-azido-5-deoxy-1,2-O-isopropylidene-Î±-D-glucurono-3,6-lactone (4) was carried out using D-glucuronolactone (1) as the starting material based on the method reported by Best et al. 2010 with some modification and subsequently, evaluated for anti-Î±-glucosidase activity. All products were characterised and identified by HPLC-ELSD, mass spectrometry (DI-ESI-MS) and NMR spectroscopy (via comparison of 1D ¹H and ¹³C data with previously reported values). The inhibitory activity of compounds 1-4 towards Î±-glucosidase from Saccharomyces cerevisiae was evaluated using the p-nitrophenyl Î±-D-glucopyranoside substrate. Compound 3 showed 29.5% inhibition followed by 2 (21.4%), 1 (15.8%) and 4 (15.7%) compared to the positive control, quercetin (72.7%).

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