Syntheses of tetrahydroxyazepanes from chiro-inositols and their evaluation as glycosidase inhibitors.
Two pairs of C(2)-symmetric tetrahydroxyazepanes [(-), (+)-1 and (-), (+)-2] have been synthesized from the enantiomeric chiro-inositols and evaluated as glycosidase inhibitors. Alternative syntheses of ido-tetrahydroxyazepanes (-)- and (+)-2 from myo-inositol were also developed. The key synthetic transformations were glycol fission and cyclization of the derived dialdehydes by double reductive amination. The D-manno-tetrahydroxyazepane [(-)-1] showed selective inhibition of alpha-L-fucosidase and beta-D-galactosidase, while the enantiomer [(+)-1] was a selective inhibitor of an alpha-D-galactosidase. In contrast, the L-ido-tetrahydroxyazepane (+)-2 was a broad spectrum hexosidase inhibitor, but showed none of the reported hexosaminidase inhibition. Its enantiomer (-)-2 is a poor hexosidase inhibitor.
Painter
Gavin F
GF
Carbohydrate Chemistry, Industrial Research Limited, PO Box 31-310, Lower Hutt, New Zealand. g.painter@irl.cri.nz
Eldridge
Paul J
PJ
Falshaw
Andrew
A
D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007294:Inositol / Q000138:chemical synthesis* / Q000494:pharmacology*; D013237:Stereoisomerism
D004791:Enzyme Inhibitors; D007294:Inositol; D006026:Glycoside Hydrolases