Department of Biotechnology, Centre for Synthetic Biology, Ghent University, Ghent, Belgium.
Department of Organic and Macromolecular Chemistry, Laboratory for Organic and Bio-Organic Synthesis (LOBOS), Ghent University, Ghent, Belgium.
J Enzyme Inhib Med Chem. 2020 Dec;35(1):1964-1989. doi: 10.1080/14756366.2020.1837125.
Although trehalose has recently gained interest because of its pharmaceutical potential, its clinical use is hampered due to its low bioavailability. Hence, hydrolysis-resistant trehalose analogues retaining biological activity could be of interest. In this study, 34 4- and 6--substituted trehalose derivatives were synthesised using an ether- or carbamate-type linkage. Their hydrolysis susceptibility and inhibitory properties were determined against two trehalases, i.e. porcine kidney and . With the exception of three weakly hydrolysable 6--alkyl derivatives, the compounds generally showed to be completely resistant. Moreover, a number of derivatives was shown to be an inhibitor of one or both of these trehalases. For the strongest inhibitors of porcine kidney trehalase IC values of around 10 mM could be determined, whereas several compounds displayed sub-mM IC against trehalase. Dockings studies were performed to explain the observed influence of the substitution pattern on the inhibitory activity towards porcine kidney trehalase.
尽管海藻糖由于其具有药物潜力而最近引起了人们的兴趣，但由于其生物利用度低，其临床应用受到了阻碍。因此，具有生物活性的水解抗性海藻糖类似物可能会引起人们的兴趣。在这项研究中，使用醚或氨基甲酸酯型键合合成了 34 种 4-和 6--取代的海藻糖衍生物。测定了它们对两种海藻糖酶（即猪肾和 ）的水解易感性和抑制特性。除了三种水解能力较弱的 6--烷基衍生物外，这些化合物通常完全具有抗性。此外，一些衍生物被证明是一种或两种这些海藻糖酶的抑制剂。对于猪肾海藻糖酶最强的抑制剂，其 IC 值约为 10mM，而几种化合物对 海藻糖酶的 IC 值则低于亚毫摩尔。进行了对接研究，以解释取代模式对猪肾海藻糖酶抑制活性的观察到的影响。
