Asymmetric synthesis and affinity of potent sialyltransferase inhibitors based on transition-state analogues.
Inhibitors that are structurally related to the transition-state model of the proposed SN1-type mechanism of sialyl transfer, exhibit particularly high binding affinities to alpha(2-6)sialyltransferases. Furthermore, replacing the neuraminyl residue with a simple aryl or hetaryl ring and substituting the carboxylate group for a phosphonate moiety, improves both binding affinity and synthetic accessibility. Herein we report on the synthesis and inhibition of a wide range of novel, potent transition-state analogue based alpha(2-6)sialyltransferase inhibitors comprising a planar anomeric carbon, an increased distance between the anomeric carbon and the CMP leaving group, and at least two negative charges. We also present a short, efficient asymmetric synthesis of the most promising benzyl inhibitors, providing rapid access to large quantities of highly potent, stereochemically-pure (>96% de) inhibitors for further biological investigation (e.g.(R)-3b, Ki = 70 nM).
Skropeta
Danielle
D
Fachbereich Chemie, Universitaet Konstanz, Fach M 725, D-78457 Konstanz, Germany. D.Skropeta@chem.usyd.edu.au
Schwörer
Ralf
R
Haag
Tobias
T
Schmidt
Richard R
RR
D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D012799:Sialyltransferases / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
D004791:Enzyme Inhibitors; D063065:Organophosphonates; D012799:Sialyltransferases; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase