Bortezomib (peptide boronic acid)

Proteasome inhibitors containing aldehyde or ketone functions react reversibly with the threonine hydroxyl to give the corresponding acetals 10.1 and 10.2. Vinyl sulfones were originally introduced as inhibitors of cysteine proteases,8 since these Michael acceptors are expected to react with soft nucleophiles like thiols, but it was subsequently found that they also form a covalent adduct 10.3 with the threonine group in the proteasome catalytic site. In the case of epoxyketones, like the natural product epoxomycin, the X-ray crystal structure and spectrometric analysis of a complex between the inhibitor and the yeast Saccharomyces cerevisiae 20S proteasome showed the formation of the morpholine derivative 10.5. The generation of this compound was explained by the formation of hemiacetal 10.4 through reaction of the threonine oxygen with the carbonyl group of the epoxyketone pharmacophore, followed by nucleophilic attack of the amino group onto the more hindered epoxide carbon atom with inversion of configuration.9

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