Scientific Results

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

Year: 2018

Authors: D’Adamio G., Forcella M., Fusi P., Parenti P., Matassini C., Ferhati X., Vanni C., Cardona F.

Autors Affiliation: [D’Adamio, Giampiero; Matassini, Camilla; Ferhati, Xhenti; Vanni, Costanza; Cardona, Francesca] Univ Florence, Dept Chem Ugo Schiff, Via Lastruccia 3-13, I-50019 Sesto Fiorentino, FI, Italy.
[Forcella, Matilde; Fusi, Paola] Univ Milano Bicocca, Dept Biotechnol & Biosci, Piazza Sci 2, I-20126 Milan, Italy.
[Parenti, Paolo] Univ Milano Bicocca, Dept Earth & Environm Sci, Piazza Sci 1, I-20126 Milan, Italy.
[Matassini, Camilla; Cardona, Francesca] CNR INO, Via N Carrara 1, I-50019 Sesto Fiorentino, FI, Italy.
[Cardona, Francesca] Univ Bari, Consorzio Interuniv Nazl Ric Metodol & Proc Innov, I-70125 Bari, Italy.

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 alpha-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 mu M 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 (alpha,beta-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 beta-glucoside 9 beta, which was active in the low micromolar range (IC50 = 0.78 mu M) and 12-fold more potent (and more selective) than 9 alpha towards the insect trehalase.

Journal/Review: MOLECULES

Volume: 23 (2)      Pages from: 436-1  to: 436-18

KeyWords: iminosugars; trehalase inhibitors; pseudodisaccharides; pyrrolizidines; pyrrolidines
DOI: 10.3390/molecules23020436

Citations: 9
data from “WEB OF SCIENCE” (of Thomson Reuters) are update at: 2021-10-17
References taken from IsiWeb of Knowledge: (subscribers only)
Connecting to view paper tab on IsiWeb: Click here
Connecting to view citations from IsiWeb: Click here

gdpr-image
This site uses cookies. If you decide to continue browsing we consider that you accept their use. For more information about cookies and how to delete them please read our Info Policy on cookies use.
Read more