A practical synthesis of kifunensine analogues as inhibitors of endoplasmic reticulum alpha-mannosidase I.

doi:10.1021/JO0516382

Paper

A practical synthesis of kifunensine analogues as inhibitors of endoplasmic reticulum alpha-mannosidase I.

Published Nov 1, 2005 · K. W. Hering, K. Karaveg, K. Moremen

The Journal of organic chemistry

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Abstract

[reaction: see text] A practical synthesis of the potent class I alpha-mannosidase inhibitor kifunensine (1) beginning from the inexpensive and readily available starting material L-ascorbic acid (15) is described. The protected amino-alcohol ((2R,3R,4R,5R)-5-amino-2,3:4,6-diisopropylidenedioxyhexanol, 11) served as a key intermediate from which several N-1 substituted kifunensine analogues (including N-methyl, N-cyclohexyl, and N-bis(hydroxymethyl)methyl) and 2-desoxakifunensine analogues (including N-H and N-methyl) were prepared and screened for inhibition of human endoplasmic reticulum alpha-mannosidase I (ER Man I) and mouse Golgi alpha-mannosidase IA (Golgi Man IA). In addition, several pseudodisaccharide kifunensine analogues in which a mannose residue was tethered to N-1 of kifunensine via a two-, three-, or four-carbon linker and an affinity-bound kifunensine analogue were also prepared and evaluated for biological activity. While the synthesized N-1 kifunesine analogues were found to be less potent inhibitors of Class I alpha-mannosidases than kifuensine itself, the bis(hydroxymethyl)methylkifunensine analogue 6 was shown to selectively inhibit ER Man I over Golgi Man IA.

Study Snapshot

Kifunensine analogues can be synthesized from L-ascorbic acid, with the bis(hydroxymethyl)methylkifunensine analogue 6 showing selective inhibition of endoplasmic reticulum alpha-mannosidase I over Golgi mannos

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

A practical synthesis of kifunensine analogues as inhibitors of endoplasmic reticulum alpha-mannosidase I.

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References

Citations

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