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.
Highlights
Carbohydrates are the most diverse and abundant biomolecules on earth, displaying a wide variety of functions[1]
The alternative 4-OH isomer 8 could be obtained via diisobutylaluminium hydride (DIBAL-H) reduction in dichloromethane: in a typical experiment, starting material still remained at moment of quenching (10% recovered), while in addition to the desired compound 8 (55%), regio-isomer 7 (19%) and product 9 (9%, resulting from overreduction) were isolated through tedious chromatographic separation
To evaluate whether the non-hydrolysable trehalose derivatives are still able to bind to the enzyme, inhibition experiments were performed with the trehalases from porcine kidney and M. smegmatis
Summary
Carbohydrates are the most diverse and abundant biomolecules on earth, displaying a wide variety of functions[1]. Interest arose in trehalose 1 (Figure 1), a disaccharide consisting of two D-glucose units linked via an a-1,1-a-bond, resulting in a molecule with unique stabilising properties[2,3] The stability of this non-reducing glucobiose is reflected by several interesting physicochemical properties like broad pH stability[4], high glass transition and melting temperatures[5,6], low hydrolysis rate[5]. Trehalose fulfils a biological role in various organisms including bacteria, yeast, fungi, insects, invertebrates and plants, it is not found in mammals[6,7] It can serve as energy and carbon source[6,7], signalling molecule[6,8,9] and cell wall building block[6,10]. It can protect organisms and compounds under stress conditions like desiccation[7,11,12], dehydration[7,13,14,15], heat[7,13], cold[7] and oxidation[7,14]
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