The Open Collections website will be undergoing maintenance on Wednesday December 7th from 9pm to 11pm PST. The site may be temporarily unavailable during this time.
UBC Theses and Dissertations
Synthesis of cyclitol-based glucosidase inhibitors Caron, Gaétan
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.
Item Citations and Data