Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 18, Issue 8, Pages 2829-2835Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2010.03.027
Keywords
Kotalanol; Isomer of kotalanol; D-Mannitol; Cyclic sulfate; Glucosidase inhibitors; Human maltase glucoamylase; Type 2 diabetes
Funding
- Canadian Institutes for Health Research [FRN79400]
- Heart and Stroke Foundation of Ontario [NA6305]
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The syntheses of an isomer of kotalanol, a naturally occurring glucosidase inhibitor, and of kotalanol itself are described. The target compounds were synthesized by nucleophilic attack of PMB-protected 1,4-anhydro-4-thio-D-arabinitol at the least hindered carbon atom of two 1,3-cyclic sulfates, which were synthesized from D-mannose. Methoxymethyl ether and isopropylidene were chosen as protecting groups. The latter group was critical to ensure the facile deprotection of the coupled products in a one-step sequence to yield kotalanol and its isomer. The stereoisomer of kotalanol, with the opposite stereochemistry at the C-6' stereogenic centre, inhibited the N-terminal catalytic domain of intestinal human maltase glucoamylase (ntMGAM) with a K-i value of 0.20 +/- 0.02 mu M; this compares to a K-i value for kotalanol of 0.19 +/- 0.03 mu M. The results indicate that the configuration at C-6' is inconsequential for inhibitory activity against this enzyme. (C) 2010 Elsevier Ltd. All rights reserved.
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