Inhibition activities of iminosugars against glycoprotein processing

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We studied the concise synthesis of DGJ and L-DGJ from L- and D-tagatose respectively in just four steps, and shows the value of the enantiomers of tagatose as chirons. As with other α-galactosidases L-DGJ was found to be an inhibitor of α-Gal A, about 1000-fold weaker than its enantiomer DGJ. L-DGJ was also found to be a chaperone for α-Gal A, again about 1000 times less active than DGJ. Non-competitive inhibition by L-DGJ is consistent with binding at a different site than DGJ which shows competitive inhibition and binds at the active site. While the inhibition of the same glycosidase by both enantiomers of an iminosugar is well-known, this is the first example of enantiomeric iminosugars acting as synergistic pharmacological chaperones for misfolded proteins; this result may indicate that binding at the active site of the enzyme is not necessary. There are many hundreds of pyrrolidine, piperidine and azepane sugar mimics but azetidines are only just beginning to be studied. There are few examples of carbohydratederived azetidines, although the properties of hydroxyazetidines are of current interest. N-Alkyl hydroxyazetidines are potent inhibitors of purine nucleoside phosphorylase with subnanomolar Ki. We studied the synthesis of an azetidine analogue of 6,7-diepicastanospermine and compares its glycosidase activity also with D-altronojirimycin.