Synthesis of C(2)-substituted manno-configured tetrahydroimidazopyridines and their evaluation as inhibitors of snail beta-mannosidase
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2003-10
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Journal Article
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Abstract
It was shown that retaining β-glucosidases and galactosidases of families 1-3 feature a strong interaction between C(2)OH of the substrate and the catalytic nucleophile. An analogous interaction can hardly take place for retaining β-mannosidases. A structure-activity comparison between the inhibition of the β-glucosidase from Caldocellum saccharolyticum (family 1) and β-glucosidase from sweet almonds by the gluco-imidazoles 1-6, and the inhibition of snail β-mannosidase by the corresponding manno-imidazoles 8-13 does not show any significant difference, suggesting that also the mechanisms of action of these glycosidases do not differ significantly. For this comparison, we synthesized and tested the manno-imidazoles 9-13, 28, 29, 32, 35, 40, 41, 43, 46, 47, and 50. Among these, the alkene 29 is the strongest known inhibitor of snail β-mannosidase (Kᵢ= 6 nM, non-competitive); the aniline 35 is the strongest competitive inhibitor (Ki=8 nM).
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86 (10)
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3482 - 3509
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Wiley‐VHCA
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Received 7 July 2003, Published online 10 November 2003.