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-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 microM) 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.
Behr
J-B
JB
Laboratoire Réactions Sélectives et Applications UMR 6519, UFR Sciences, CNRS, BP 1039, 51687 Reims Cedex 2, France. jb.behr@univ-reims.fr
Gainvors-Claisse
A
A
Belarbi
A
A
D000470:Alkaloids / Q000138:chemical synthesis* / Q000494:pharmacology*; D002687:Chitin Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology*; D011763:Pyrrolizidine Alkaloids / Q000138:chemical synthesis* / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D013237:Stereoisomerism
D000470:Alkaloids; D004791:Enzyme Inhibitors; D011758:Pyrroles; D011763:Pyrrolizidine Alkaloids; C409108:casuarine; D002687:Chitin Synthase; D006026:Glycoside Hydrolases