The Reactivity of α‐Fluorinated Mono‐ and Diketones Uncovers their Potential as Electrophilic Warheads for Reversible Covalent Drugs

The potential of fluorinated mono- and diketones as electrophilic warheads for reversible covalent drugs is described by studying their equilibria reactions with the protected nucleophilic amino acids serine, cysteine and lysine.

Fluorinated diketones (FDKs) are electrophilic moieties holding unique molecular properties that make them potential reversible and multifaceted covalent warheads for drug design. To further explore this potential, the multicomponent equilibrium systems of various fluorinated monoketones (FMKs) and FDKs in the presence of the relevant nucleophilic amino acids serine, cysteine, and lysine are studied. These equilibrium systems are investigated using ¹⁹ F- and ¹³C- NMR spectroscopy, and reveal that for both cysteine and lysine most of the FMKs and FDKs studied may potentially serve as electrophilic warheads for reversible covalent drugs.

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