Probing the active-site requirements of human intestinal N-terminal maltase-glucoamylase: Synthesis and enzyme inhibitory activities of a six-membered ring nitrogen analogue of kotalanol and its de-O-sulfonated derivative

In order to probe the active-site requirements of the human N-terminal subunit of maltase-glucoamylase (ntMGAM), one of the clinically relevant intestinal enzymes targeted for the treatment of type-2 diabetes, the syntheses of two new inhibitors are described. The target compounds are structural hybrids of kotalanol, a naturally occurring glucosidase inhibitor with a unique five-membered ring sulfonium-sulfate inner salt structure, and miglitol, a six-membered ring antidiabetic drug that is currently in clinical use. The compounds comprise the six-membered ring of miglitol and the side chain of kotalanol or its de-O-sulfonated derivative. Inhibition studies of these hybrid molecules with human ntMGAM indicated that they are inhibitors of this enzyme with comparable Ki values to that of miglitol (kotalanol analogue: 2.3 ± 0.6 μM; corresponding de-O-sulfonated analogue: 1.4 ± 0.5 μM; miglitol: 1.0 ± 0.1 μM). However, they are less active compared to kotalanol (Ki = 0.19 ± 0.03 μM). These results suggest that the 3T2 enzyme-bound conformation of the five-membered thiocyclitol moiety of the kotalanol class of compounds more closely resembles the 4H3 conformation of the proposed transition state for the formation of an enzyme–substrate covalent intermediate in the glycosidase hydrolase family 31 (GH31)-catalyzed reaction.

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