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 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.
Subject(s)
Alkaloids/chemical synthesis , Alkaloids/pharmacology , Chitin Synthase/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Pyrrolizidine Alkaloids/chemical synthesis , Pyrrolizidine Alkaloids/pharmacology , Chitin Synthase/metabolism , Glycoside Hydrolases/antagonists & inhibitors , Glycoside Hydrolases/metabolism , Inhibitory Concentration 50 , Molecular Structure , Saccharomyces cerevisiae/enzymology , StereoisomerismABSTRACT
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.
Subject(s)
Chitin Synthase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Imino Sugars/pharmacology , Pyrrolizidine Alkaloids/pharmacology , Alkaloids/chemistry , Alkaloids/pharmacology , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Glycoside Hydrolases/antagonists & inhibitors , Imino Sugars/chemical synthesis , Imino Sugars/chemistry , Inhibitory Concentration 50 , Kinetics , Molecular Structure , Pyrroles/chemistry , Pyrroles/pharmacology , Pyrrolizidine Alkaloids/chemical synthesis , Pyrrolizidine Alkaloids/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The synthesis and biological evaluation of a new UDP-GlcNAc competitor (I), designed to mimic the transition state of the sugar donor in the enzymatic reaction catalysed by chitin synthetase, is described. Compound (I) was found to competitively inhibit chitin synthetase from Saccharomyces cerevisiae with respect to UDP-GlcNAc, but displayed minimal antifungal activity.
Subject(s)
Aminoglycosides , Chitin Synthase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Saccharomyces cerevisiae/enzymology , Uridine Diphosphate N-Acetylglucosamine/analogs & derivatives , Uridine Diphosphate N-Acetylglucosamine/pharmacology , Anti-Bacterial Agents/pharmacology , Antifungal Agents/pharmacology , Binding Sites , Chitin Synthase/chemistry , Enzyme Inhibitors/chemistry , Kinetics , Pyrimidine Nucleosides/pharmacology , Structure-Activity Relationship , Uridine Diphosphate N-Acetylglucosamine/chemical synthesis , Uridine Diphosphate N-Acetylglucosamine/chemistryABSTRACT
We report here the design, synthesis and antifungal evaluation of a new model of bisubstrate analogue inhibitor for glycosyltransferases. The synthetic strategy relies on the reductive amination between the aldehyde derived from an N-allylphosphono-pyrrolidine and an aminosugar.
