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

A series of polyhydroxy-pyrrolizidines were designed as constrained analogues of 6-deoxyhomoDMDP, a potent naturally occurring inhibitor of chitin synthase. Enzymatic evaluation revealed that 7-deoxycasuarine was the best inhibitor of the series (IC50 = 820 mu M) displaying a non-competitive 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 biological evaluation towards glycosidases of these synthetic casuarine analogues is also disclosed.