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 microM) 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.
Behr
J B
JB
Laboratoire Réactions Sélectives et Applications UMR 6519, UFR Sciences - CNRS, BP 1039, 51687 Reims 2, France. jb.behr@univ-reims.fr
Gainvors-Claisse
A
A
Belarbi
A
A
D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology; D002687:Chitin Synthase / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors; D050111:Imino Sugars / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007700:Kinetics; D015394:Molecular Structure; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D011763:Pyrrolizidine Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000470:Alkaloids; D004791:Enzyme Inhibitors; D050111:Imino Sugars; D011758:Pyrroles; D011763:Pyrrolizidine Alkaloids; C409108:casuarine; D002687:Chitin Synthase; D006026:Glycoside Hydrolases