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Synthesis, trehalase hydrolytic resistance and inhibition properties of 4-and 6-substituted trehalose derivatives

Shari Dhaene (UGent) , Johan Van der Eycken (UGent) , Koen Beerens (UGent) , Jorick Franceus (UGent) , Tom Desmet (UGent) and Jurgen Caroen (UGent)
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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.
Keywords
Pharmacology, Drug Discovery, General Medicine, Trehalose derivatives, trehalase, inhibition, hydrolytic resistance, molecular dockings, DESICCATION TOLERANCE, CHEMICAL CHAPERONE, MOUSE MODEL, LENTZTREHALOSES

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MLA
Dhaene, Shari, et al. “Synthesis, Trehalase Hydrolytic Resistance and Inhibition Properties of 4-and 6-Substituted Trehalose Derivatives.” JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, vol. 35, no. 1, 2020, pp. 1964–89, doi:10.1080/14756366.2020.1837125.
APA
Dhaene, S., Van der Eycken, J., Beerens, K., Franceus, J., Desmet, T., & Caroen, J. (2020). Synthesis, trehalase hydrolytic resistance and inhibition properties of 4-and 6-substituted trehalose derivatives. JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 35(1), 1964–1989. https://doi.org/10.1080/14756366.2020.1837125
Chicago author-date
Dhaene, Shari, Johan Van der Eycken, Koen Beerens, Jorick Franceus, Tom Desmet, and Jurgen Caroen. 2020. “Synthesis, Trehalase Hydrolytic Resistance and Inhibition Properties of 4-and 6-Substituted Trehalose Derivatives.” JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY 35 (1): 1964–89. https://doi.org/10.1080/14756366.2020.1837125.
Chicago author-date (all authors)
Dhaene, Shari, Johan Van der Eycken, Koen Beerens, Jorick Franceus, Tom Desmet, and Jurgen Caroen. 2020. “Synthesis, Trehalase Hydrolytic Resistance and Inhibition Properties of 4-and 6-Substituted Trehalose Derivatives.” JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY 35 (1): 1964–1989. doi:10.1080/14756366.2020.1837125.
Vancouver
1.
Dhaene S, Van der Eycken J, Beerens K, Franceus J, Desmet T, Caroen J. Synthesis, trehalase hydrolytic resistance and inhibition properties of 4-and 6-substituted trehalose derivatives. JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY. 2020;35(1):1964–89.
IEEE
[1]
S. Dhaene, J. Van der Eycken, K. Beerens, J. Franceus, T. Desmet, and J. Caroen, “Synthesis, trehalase hydrolytic resistance and inhibition properties of 4-and 6-substituted trehalose derivatives,” JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, vol. 35, no. 1, pp. 1964–1989, 2020.
@article{8693376,
  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.}},
  author       = {{Dhaene, Shari and Van der Eycken, Johan and Beerens, Koen and Franceus, Jorick and Desmet, Tom and Caroen, Jurgen}},
  issn         = {{1475-6366}},
  journal      = {{JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY}},
  keywords     = {{Pharmacology,Drug Discovery,General Medicine,Trehalose derivatives,trehalase,inhibition,hydrolytic resistance,molecular dockings,DESICCATION TOLERANCE,CHEMICAL CHAPERONE,MOUSE MODEL,LENTZTREHALOSES}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{1964--1989}},
  title        = {{Synthesis, trehalase hydrolytic resistance and inhibition properties of 4-and 6-substituted trehalose derivatives}},
  url          = {{http://dx.doi.org/10.1080/14756366.2020.1837125}},
  volume       = {{35}},
  year         = {{2020}},
}

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