Cystein Bioconjugation and Togni Reagents

Already in the first years after the original hypervalent iodine-CF3 reagents were discovered (the so-called Togni-CF3 reagents), it was clear that the exceptional reactivity towards thiols could be used for modification of cysteine side chains which can lead to advantageous modification (cysteine blocking, 19F-NMR probes, etc.)

 

biothiol trifluoromethylationThe robust, quick and chemoselective trifluoromethylation of thiols enabled to synthetize various complex S-CF3 containing biomolecules in one step without any protective groups.

late stage tfm

 

Advantages of trifluoromethylative cysteine blocking

There are several advantages of cystein trifluoromethylation in comparison with other alternatives (iodoacetamides, N-alkylmaleimides).

  • Very high reaction rate (minutes at 0 °C)
  • Irreversible tagging (maleimides can sometimes engage in retro-Michael reaction)
  • No lysine modification (solvent accessible lysines can engage in alkylation by iodoacetamide or add to maleimides)
  • Installation of a unique and symmetrical fluorinated label useful for tracking

 

Hypervalent iodine-CF2CF2X reagents as new cystein selective bioconjugation reagents

In the recent publication, Matoušek et al.[1] described the first example of S-fluoroalkylation of a cystein derivative using a hypervalent iodine-CF2CF2X reagent bearing a fluorescent unit X.

The tagging reaction was finished in less than 2 h at –40 °C with just 1,5 equivalents of the reagent affording 90% NMR yield of the conjugate that was isolated in 72% yield.

 

pyrene fluoroalkylation cystein derivativeMoreover, the authors showed that the conjugate was stable towards 50 equivalents of highly nucleophilic aliphatic thiol after 72 hours.

These impressive preliminary results suggest that these new hypervalent iodine-CF2CF2X reagents could act as extremely efficient tools for cystein bioconjugation.

The chemoselectivity, irreversibility and high reaction rate could make these reagents an ideal candidate for construction of cysteine-bound antibody drug conjugates.

More sophisticated reagents that enable to install a wider variety of motifs will be soon published and offered.

more sophisticated CF2CF2 reagentsReferences:

  1. V. Matoušek, J. Václavík, P. Hájek, J. Charpentier, Z. E. Blastik, E. Pietrasiak, A. Budinská, A. Togni, P. Beier, Chemistry – A European Journal 2016, 22, 417-424.

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