Polyhydroxylated azetidine iminosugars: Synthesis,glycosidase inhibitory activity and molecular docking studies |
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Authors: | Pravin P. Lawande Vyankat A. Sontakke Navanath M. Kumbhar Tanay R. Bhagwat Sougata Ghosh Vaishali S. Shinde |
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Affiliation: | 1. Department of Chemistry, Savitribai Phule Pune University (Formerly, University of Pune), Pune 411007, India;2. Department of Microbiology, Modern College of Arts, Science and Commerce, Savitribai Phule Pune University, Ganeshkhind, Pune 411016, India |
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Abstract: | An efficient and practical strategy for the synthesis of unknown azetidine iminosugars (2S,3R,4S)-2-((R)-1,2-dihydroxyethyl)-3-hydroxy-4-(hydroxymethyl)azetidine 2, (2S,3r,4R)-3-hydroxy-2,4-bis(hydroxymethyl)azetidine 3 and (2S,3R,4S)-3-hydroxy-4-(hydroxymethyl)-N-methylazetidine-2-carboxylic acid 4, starting from the d-glucose has been reported. The methodology involves preparation of the 3-amino-N-benzyloxycarbonyl-3-deoxy-6-O-tert-butyldimethylsillyl-1,2-O-isopropylidene-α-d-glucofuranose 9, which was converted to the C-5-OMs derivative 11. Intramolecular nucleophilic displacement of the C-5-OMs group with in situ generated 3-amino functionality provided the required key azetidine ring skeletons 10 with additional hydroxymethyl group. Removal of 1,2-acetonide protection, followed by reduction and hydrogenolysis afforded azetidine iminosugar 2. Alternatively, removal of 1,2-acetonide group and chopping of C1-anomeric carbon gave C2-aldehyde that on reduction or oxidation followed by hydrogenolysis gave 2,4-bis(hydroxymethyl) azetidine iminosugars 3 and N-methylazetidine-2-carboxylic acid 4 respectively. The glycosidase inhibitory activity of 2–4 iminosugars was screened against various glycosidase enzymes and compared with a standard miglitol. Amongst synthesized targets, the compound 2 was found to be more potent amyloglucosidase inhibitor than miglitol. These results were supported by molecular docking studies. |
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Keywords: | Polyhydroxylated azetidines Iminosugars Glycosidase inhibitory activity Nucleophilic displacement reaction Corresponding author. |
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