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Synthesis of cyclitol-based glucosidase inhibitors

University of British Columbia

The first conduritol aziridine (1,2-dideoxy-1,2-epimino-myo-inositol, 1) was synthesized in seven steps from myo-inositol (2) and inhibits pABG5 β-glucosidase and yeast ⍺-glucosidase irreversibly. 1,2-0-Cyclohexylidene-myo-inositol (3) was obtained by reaction of 2 with cyclohexanone. Benzylation of 3 followed by hydrolysis of the ketal gave l,4,5,6-tetra-0-benzyl-myo-inositol (5). The two free hydroxyl groups in 5 were methanesulfonylated and the axial mesyl group in l,4,5,6-tetra-0-benzyl-2,3-di-0-methanesulfonyl-myo-inositol (12) was selectively displaced by an azido group. The resulting 1-azido-2,3,4,5-tetxa-0-benzyl-1-deoxy-6-0-methanesulfonyl-scyllo-inositol (13) was hydrogenated in the presence of HC1 to give 1-amino-1-deoxy-2-0-methanesulfonyl-scyllo-inositol (24) hydrochloride. Cyclisation of 24 under basic aqueous conditions yielded DL-1. [Formula Omitted] The dissociation constant Ki and the inactivation rate constant ki for inactivation of pABG5 β-glucosidase by 1 were calculated to be 3.0 mM and 0.077 min⁻¹ respectively. For yeast ⍺-glucosidase inactivation, values of Ki, and ki were found to be 9.5 mM and 0.39 min-1 respectively. Finally, 24 and 31 were tested as reversible (non-covalent) inhibitors of both the glucosidases and the respective inhibition constants (Ki) determined.

Text

2010-08-28

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http://hdl.handle.net/2429/27852

Chemistry

University of British Columbia

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