New synthesis and biological evaluation of uniflorine A derivatives: towards specific insect trehalase inhibitors

Year: 2015

Authors: D’Adamio G., Sgambato A., Forcella M., Caccia S., Parmeggiani C., Casartelli M., Parenti P., Bini D., Cipolla L., Fusi P., Cardona F.

Autors Affiliation: Univ Florence, Dipartimento Chim Ugo Schiff, I-50019 Sesto Fiorentino, FI, Italy; Univ Milano Bicocca, Dept Biotechnol & Biosci, I-20126 Milan, Italy; Univ Milan, Dept Biosci, I-20133 Milan, Italy; UOS Sesto Fiorentino, CNR INO, I-50019 Sesto Fiorentino, FI, Italy; LENS, I-50019 Sesto Fiorentino, FI, Italy; Univ Milano Bicocca, Dipartimento Sci Ambiente & Terr & Sci Terra, I-20126 Milan, Italy.

Abstract: 7-Deoxy-uniflorine A (6), synthesized ex novo with a straightforward and simple strategy, and the analogues 4, 5 and 7, were evaluated as potential inhibitors of insect trehalase from Chironomus riparius and Spodoptera littoralis. All the compounds were tested against porcine trehalase as the mammalian counterpart and a-amylase from human saliva as a relevant glucolytic enzyme. The aim of this work is the identification of the simplest pyrrolizidine structure necessary to impart selective insect trehalase inhibition, in order to identify new specific inhibitors that can be easily synthesized compared to our previous reports with the potential to act as non-toxic insecticides and/or fungicides. All the derivatives 4-7 proved to be active (from low micromolar to high nanomolar range activity) towards insect trehalases, while no activity was observed against a-amylase. In particular, the natural compound uniflorine A and its 7-deoxy analogue were found to selectively inhibit insect trehalases, as they are inactive towards the mammalian enzyme. The effect of compound 6 was also analyzed in preliminary in vivo experiments. These new findings allow the identification of natural uniflorine A and its 7-deoxy analogue as the most promising inhibitors among a series of pyrrolizidine derivatives for future development in the agrochemical field, and the investigation also outlined the importance of the stereochemistry at C-6 of pyrrolizidine nucleus to confer such enzyme specificity.

Journal/Review: ORGANIC & BIOMOLECULAR CHEMISTRY

Volume: 13 (3)      Pages from: 886  to: 892

More Information: We gratefully acknowledge University of Milano-Bicocca, FAR 2009 and PRIN 2010-2011, 2010L9SH3 K 006.
KeyWords: Chironomus-riparius Larvae; Pyrrolizidine; Stereoisomers; Trehazolin; Casuarine; Alpha
DOI: 10.1039/c4ob02016b

Citations: 18
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