Sydnone-modified neuraminic acids for a more selective metabolic oligosaccharide engineering of living cells

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Monday, July 1, 2019 - 12:15 to 12:30

Frederic Friscourt1,2

1Institut Européen De Chimie Et Biologie, Université De Bordeaux, Pessac, France, 2INCIA, CNRS UMR5287, Bordeaux, France

The bioorthogonal chemical reporter strategy, which elegantly combines the use of metabolically labeled azido-sugars and 1,3-dipolar cycloadditions with strained alkynes, is emerging as a versatile technology for the labeling and visualization of glycans.[1] Advantages of cyclooctyne-based probes encompass their high reactivity, non-toxicity (metal-free conditions) and synthetic modularity. However, the azido-reporter is not completely biologically inert as it can react, to varying degrees, with biological functionalities such as thiols.[2] This inherent instability makes the azide functionality a precursor for the potential accumulation of secondary metabolites with unknown biological effects. 

In order to address this limitation, while keeping the advantages of the cyclooctyne framework as the reactive probe, we decided to investigate the utilization of other stable 1,3-dipoles as novel reporters. In this context, we present herein the utilization of 3,4-disubstituted sydnones, a singular class of aromatic mesoionic dipoles, as novel chemical reporters[3] for the metabolic oligosaccharide engineering (MOE) of sialoconjugates in living cells (Figure).[4]

The positioning of the reporter on the neuraminic acid was found to significantly alter its metabolic fate. Further in vitro enzymatic assays revealed that the 9-modified neuraminic acid is preferentially accepted by the sialyltransferase ST6Gal-I over ST3Gal-IV, leading to the favored incorporation of the reporter into linkage-specific 2,6-N-linked sialoproteins. Due to its high biological stability and more selective glycan incorporation, this novel chemical reporter will significantly expand our chemical biology toolbox for investigating the roles of specific sialosides. 

Overview of sulfoquinovose metabolism

  1. Friscourt, F.; Boons, G. J. Bioorthogonal reactions for labeling glycoconjugates in Click chemistry in glycoscience: New developments and strategies 2013, 211.
  2. Lin, V. S.; Chen, W.; Xian, M.; Chang, C. J. Chem. Soc. Rev. 2015, 44, 4596-4618.
  3. (a) Favre, C.; de Cremoux, L.; Badaut, J.; Friscourt F. J. Org. Chem. 2018, 83, 2058-2066; (b) Favre, C.; Friscourt F. Org. Lett. 2018, 20, 4213-4217.
  4. Chinoy, Z. S.; Bodineau, C.; Favre, C.; Moremen, K. W.; Durán, R. V.; Friscourt, F. Angew. Chem. Int. Ed. 2019, DOI: 10.1002/anie.201814266.