Inspired by DAR-DIA-076fb6ea; rather than a covalent bond to Cys, can we have a more subtle electrostatic SH------F interaction to aid potency? CF3 had best balance of binding with 220CySH in p53-Y220C binding in an earlier study of ours and lowest desolvation penalties so gave most potent binder. See Spencer et al. DOI: 10.1021/acschembio.6b00315; ACS Chem. Biol. 2016, 11, 2265−2274.
As pointed out earlier; CH2FCH2-N can give FCH2CO2H...... after oxid metabolism. Adding a CF3CH2 group to an amine can be problematic; we've observed loss of HF and formation of an iodoalkene with CF3CH2I !!! CF3CH2OTs was a good alkylating agent!