Inhibition of chitin synthase by a series of 7-deoxycasuarine stereoisomers designed as constrained analogues of the potent inhibitor 6-deoxyhomoDMDP

Abstract

A series of polyhydroxy-pyrrolizidines were designed as constrained analogues of 6-deoxy-homoDMDP, a potent naturally occurring inhibitor of chitin synthase. Enzymatic evaluation revealed that 7-deoxycasuarine was the best inhibitor of the series (IC₅₀ = 820 µM) displaying a noncompetitive inhibition pattern, whereas the other tested compounds had IC₅₀ in the range 4.3–18.9 mM. This is the first report of pyrrolizidine-type iminosugars inhibiting a glycosyltransferase. In addition, the inhibitory potencies towards glycosidases of these synthetic casuarine analogues is also disclosed.

Keywords:

• Chitin synthase
• Inhibition
• Iminosugars
• Pyrrolizidines

Acknowledgements

The authors gratefully acknowledge Prof. P. Vogel, Ecole Polytechnique Fédérale de Lausanne, Switzerland, for the enzymatic evaluation towards glycosidases.