Developing carbocyclic activity-based probes for sialidases

Session: 
S1.1 Chemical biology tools
Code: 
OL1.1.4
Location (hall): 
Glucose
Start/end time: 
Monday, July 1, 2019 - 12:30 to 12:45
Pieter
de Saint Aulaire

Pieter de Saint Aulaire1, Jorin Hoogenboom1, Tom Wennekes1

1Universiteit Utrecht, Utrecht, The Netherlands

Sialic acids are a class of monosaccharides that occur on the termini of a wide range of glycans and are vital in intercellular communication. Sialidase enzymes are glycosidases that cleave sialic acids from these glycans and are distributed in various kinds of organisms. Sialidase activity is involved in various diseases[1] that are not yet fully understood and therefore sialidases are an attractive target to study and perturb. Based on the succesfull design of carbocyclic covalent inhibitors and activity-based probes (ABPs) for other glycosdases by Overkleeft et al.[2] we have developed a synthetic route for carbocyclic ABPs for sialidases that we are currently evaluating for its ability to inactivate sialidases.

With the goal of synthesising the carbocyclic epoxide(1, 3) and aziridine(2, 4) mimics of neuraminic acid, we developed a synthetic route starting from a chiral furanone towards a key intermediate allowing for ring closing metathesis[3]. Using a specialised Grubbs catalyst for sterically hindered systems, ring closing metathesis yielded a carbocycle with the desired stereochemistry for neuraminic acid. Further transformations of this carbocycle lead to the covalent sialidase inhibitors 1 and 3 and ABPs 2 and 4.

Sialidase inhibitors and ABPs and the synthetic approach towards them

References: 
  1. A. N. Orekhov et al. European Journal of Pharmacology, 2019, 842, 345
  2. H. S. Overkleeft et al. Nature Chemical Biology, 2010, 6, 907
  3. J. Hoogenboom Molecular design, synthesis and evaluation of chemical biology tools 2017

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