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 K(i) values to that of miglitol (kotalanol analogue: 2.3±0.6μM; corresponding de-O-sulfonated analogue: 1.4±0.5μM; miglitol: 1.0±0.1μM). However, they are less active compared to kotalanol (K(i)=0.19±0.03μM). These results suggest that the (3)T(2) enzyme-bound conformation of the five-membered thiocyclitol moiety of the kotalanol class of compounds more closely resembles the (4)H(3) conformation of the proposed transition state for the formation of an enzyme-substrate covalent intermediate in the glycosidase hydrolase family 31 (GH31)-catalyzed reaction.
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6.
Sankar
S
Mohan
Lyann
L
Sim
David R
DR
Rose
B Mario
BM
Pinto
D017485:1-Deoxynojirimycin / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005944:Glucosamine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D065089:Glycoside Hydrolase Inhibitors; D006801:Humans; D007422:Intestines / Q000201:enzymology; D007700:Kinetics; D009005:Monosaccharides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009584:Nitrogen / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013431:Sulfates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013450:Sulfones / Q000737:chemistry*; D000520:alpha-Glucosidases / Q000737:chemistry / Q000378:metabolism
D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; C114502:Kotalanol; D009005:Monosaccharides; D013431:Sulfates; D013450:Sulfones; C501633:deoxynojirimycine; D017485:1-Deoxynojirimycin; D000520:alpha-Glucosidases; D005944:Glucosamine; D009584:Nitrogen