Probing the Influence of Linker Length and Flexibility in the Design and Synthesis of New Trehalase Inhibitors

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Giampiero D'AdamioFrancesca Cardona

Abstract

This work aims to synthesize new trehalase inhibitors selective towards the insect trehalase versus the porcine trehalase, in view of their application as potentially non-toxic insecticides and fungicides. The synthesis of a new pseudodisaccharide mimetic 8, by means of a stereoselective α-glucosylation of the key pyrrolizidine intermediate 13, was accomplished. The activity of compound 8 as trehalase inhibitor towards C.riparius trehalase was evaluated and the results showed that 8 was active in the μM range and showed a good selectivity towards the insect trehalase. To reduce the overall number of synthetic steps, simpler and more flexible disaccharide mimetics 9-11 bearing a pyrrolidine nucleus instead of the pyrrolizidine core were synthesized. The biological data showed the key role of the linker chain's length in inducing inhibitory properties, since only compounds 9 (α,β-mixture), bearing a two-carbon atom linker chain, maintained activity as trehalase inhibitors. A proper change in the glucosyl donor-protecting groups allowed the stereoselective synthesis of the β-glucoside 9β, which was active in the low micromolar range (IC50 = 0.78 μM) and 12-fold more potent (and more selective) than 9α towards the insect trehalase.

References

Feb 27, 2003·The Journal of Experimental Biology·Gerhard WegenerOsamu Ando
Mar 11, 2003·Glycobiology·Alan D ElbeinDavid Carroll
May 13, 2010·Chemical Communications : Chem Comm·Francesca CardonaTracey M Gloster
Apr 18, 2012·Beilstein Journal of Organic Chemistry·Davide BiniLaura Cipolla
Nov 20, 2014·Organic & Biomolecular Chemistry·Giampiero D'AdamioFrancesca Cardona

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Citations

Oct 18, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Qing-Kun WuYue-Mei Jia
Jul 8, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Camilla MatassiniFrancesca Cardona
Jul 11, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Philippe Compain

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Methods Mentioned

BETA
glucosylation
column chromatography
glycosylation
NMR

Software Mentioned

Cary Win UV
Sigma Plot

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