Abstract

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-O-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 Mycobacterium smegmatis. With the exception of three weakly hydrolysable 6-O-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 IC₅₀ values of around 10 mM could be determined, whereas several compounds displayed sub-mM IC₅₀ against M. smegmatis trehalase. Dockings studies were performed to explain the observed influence of the substitution pattern on the inhibitory activity towards porcine kidney trehalase.

摘要

尽管海藻糖由于其药物潜力最近已引起人们的兴趣，但由于其生物利用度低而阻碍了其临床应用。因此，保持生物活性的耐水解的海藻糖类似物可能是令人感兴趣的。在这项研究中，使用醚或氨基甲酸酯型键合成了34种4-和6- O取代的海藻糖衍生物。测定了它们对两种海藻糖酶的水解敏感性和抑制特性，即猪肾和耻垢分枝杆菌。除了三个弱水解的6- O-烷基衍生物，该化合物通常显示出完全抗性。此外，许多衍生物被证明是这些海藻糖酶之一或两者的抑制剂。对于猪肾海藻糖酶的最强抑制剂，可以测定约₅₀ mM的IC ₅₀值，而几种化合物显示出针对耻垢分枝杆菌海藻糖酶的亚mM IC _50值。进行了对接研究以解释观察到的取代模式对猪肾海藻糖酶抑制活性的影响。