This research investigates the physicochemical properties of fluorinated diketones (FDKs) and their potential as reversible covalent warheads for drug development. The study reveals the CF2(CO)2 group's multifaceted nature, showing it can exist in multiple forms in equilibrium in water/octanol systems. A novel 19F-NMR-based method allowed for species-specific lipophilicity determination, revealing lipophilic to hydrophilic shifts depending on the environment. These findings, supported by DFT studies and NMR spectroscopy, suggest the CF2(CO)2 group's adaptability to diverse physiological environments and its potential for flexible regio-reactivity toward cysteine residues.

Ishay Columbus, Lee Ghindes-Azaria, Ido Michael Herzog, Eliav Blum, Galit Parvari, Yoav Eichen, Yoram Cohen, Eytan Gershonov, Eyal Drug, Sigal Saphier, Shlomi Elias, Boris Smolkin, Yossi Zafrani