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.)
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. 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.
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.
- 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.