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Asymmetric synthesis and affinity of potent sialyltransferase inhibitors based on transition-state analogues

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Abstract

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 α(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 α(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, K i = 70 nM). Published in 2003.

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Authors
  1. Danielle Skropeta
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  2. Ralf Schwörer
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  3. Tobias Haag
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  4. Richard R. Schmidt
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Skropeta, D., Schwörer, R., Haag, T. et al. Asymmetric synthesis and affinity of potent sialyltransferase inhibitors based on transition-state analogues. Glycoconj J 21, 205–219 (2004). https://doi.org/10.1023/B:GLYC.0000045093.96413.62

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  • DOI: https://doi.org/10.1023/B:GLYC.0000045093.96413.62

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