Inhibition activities of iminosugars against glycoprotein processing

我们分别以L和D-塔格糖为原料，通过四步反应简捷地合成了DGJ和L-DGJ，揭示了塔格糖对映体作为手性试剂的价值。与其他α-半乳糖苷酶一样，L-DGJ被发现是α-GalA的抑制剂，比其对映体DGJ弱约1000倍。L-DGJ也被发现是α-GalA的伴侣，同样是DGJ活性的1,000倍。L-DGJ的非竞争性抑制与DGJ在不同部位的结合一致，表现为竞争性抑制，结合在活性部位。虽然亚氨糖的两个对映体对同一糖苷酶的抑制是众所周知的，但这是第一个对错误折叠的蛋白质起到协同药理伴侣作用的对映体亚氨糖；这一结果可能表明在酶的活性部位结合是不必要的。有数以百计的吡咯烷、哌啶和氮杂环糖的模拟物，但氮杂环丁烷的研究才刚刚开始。尽管羟基氮杂环丁烷的性质目前很受关注，但碳水化合物衍生的氮杂环丁烷的例子很少。N-烷基羟基氮杂环丁烷是具有亚纳摩尔KI的嘌呤核苷磷酸化酶的有效抑制剂。我们研究了6，7-二胞蛇毒的氮杂环丁烷类似物的合成，并与D-阿曲诺吉利霉素进行了糖苷酶活性的比较。

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.