• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Chemistry: A European journal >Sp ~2-iminosugar O-, S-, and N-glycosides as conformational mimics of α-linked disaccharides; Implications for glycosidase inhibition
【24h】

Sp ~2-iminosugar O-, S-, and N-glycosides as conformational mimics of α-linked disaccharides; Implications for glycosidase inhibition

机译：Sp〜2-亚氨基糖O-，S-和N-糖苷为α-连接二糖的构象模拟物;对糖苷酶抑制的影响

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The synthesis of mimics of the α(1→6)- and α(1→4)- linked disaccharides isomaltose and maltose featuring a bicyclic sp ~2-iminosugar nonreducing moiety O-, S-, or N-linked to a glucopyranoside residue is reported. The strong generalized anomeric effect operating in sp ~2-iminosugars determines the α-stereochemical outcome of the glycosylation reactions, independent of the presence or not of participating protecting groups and of the nature of the heteroatom. It also imparts chemical stability to the resulting aminoacetal, aminothioacetal, or gem-diamine functionalities. All the three isomaltose mimics behave as potent and very selective inhibitors of isomaltase and maltase, two α-glucosidases that bind the parent disaccharides either as substrate or inhibitor. In contrast, large differences in the inhibitory properties were observed among the maltose mimics, with the O-linked derivative being a more potent inhibitor than the N-linked analogue; the S-linked pseudodisaccharide did not inhibit either of the two target enzymes. A comparative conformational analysis based on NMR and molecular modelling revealed remarkable differences in the flexibility about the glycosidic linkage as a function of the nature of the linking atom in this series. Thus, the N-pseudodisaccharide is more rigid than the O-linked derivative, which exhibits conformational properties very similar to those of the natural maltose. The analogous pseudothiomaltoside is much more flexible than the N- or O-linked derivatives, and can access a broader area of the conformational space, which probably implies a strong entropic penalty upon binding to the enzymes. Together, the present results illustrate the importance of taking conformational aspects into consideration in the design of functional oligosaccharide mimetics. Flexibility is key! Mimicking the conformational behavior of oligosaccharides is critical to the design of selective inhibitors of glycosidases. Matching the structural features of the glycone and aglycone moieties is not sufficient if the flexibility about the intersaccharide linkage does not satisfy the natural partner, even if there is extensive overlap of the respective available conformational spaces (see scheme).
机译：α（1→6）-和α（1→4）-连接的二糖异麦芽糖和麦芽糖的模拟物的合成，其特征是双环sp〜2-亚氨基糖非还原性部分O-，S-或N-连接至吡喃葡萄糖苷残基被报道。在sp〜2-亚氨基糖中发挥的强力广义异头作用决定了糖基化反应的α-立体化学结果，而与参与的保护基团是否存在以及杂原子的性质无关。它还赋予所得的氨基缩醛，氨基硫缩醛或gem-二胺官能度化学稳定性。三种异麦芽糖模拟物均表现为异麦芽糖酶和麦芽糖酶的有效且非常选择性的抑制剂，这两种α-葡萄糖苷酶与母体二糖结合，可作为底物或抑制剂。相反，在麦芽糖模拟物中观察到抑制特性的很大差异，O-连接的衍生物比N-连接的类似物更有效。 S-连接的假二糖不抑制两种靶酶中的任何一种。基于NMR和分子建模的比较构象分析显示，糖苷键的柔性随该系列中连接原子的性质而显着不同。因此，N-假二糖比O-连接的衍生物更坚硬，O-连接的衍生物表现出与天然麦芽糖非常相似的构象特性。类似的拟硫代麦芽糖苷比N-或O-连接的衍生物具有更大的柔韧性，并且可以进入更大的构象空间区域，这可能意味着与酶结合后会产生很强的熵损失。总之，本发明结果说明了在功能性低聚糖模拟物的设计中考虑构象方面的重要性。灵活性是关键！模仿寡糖的构象行为对糖苷酶选择性抑制剂的设计至关重要。如果关于糖间键的柔性不满足天然配偶体的要求，即使各个可用的构象空间有很大的重叠，匹配甘氨酸和糖苷配基部分的结构特征是不够的。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号