"MIDA masking" of boronic acid therapeutics for enhanced stability and economy.

Boronic acids are invaluable chemical reagents that enable the synthesis of complex organic molecules and are uniquely leveraged by medicinal chemists to target biological nucleophiles via an electrophilic boron center, thereby functioning as reversible covalent inhibitors. Despite their prevalence, boronic acids remain difficult to purify and are notoriously unstable in the presence of air, moisture, and reactive oxygen species-a major impediment to biological applications. We reasoned that the boronic acid protecting group N-methyliminodiacetic acid (MIDA), typically restricted to synthetic organic chemistry, could offer a superior protection strategy for boronic acid-containing bioactive molecules. Using the FDA-approved anticancer proteasome inhibitors bortezomib and ixazomib as proof-of-concept substrates, we demonstrate a several-hundred-fold increase in hydrolytic stability of a MIDA boronate compared to the current standard (e.g., diols and α-hydroxy acid protecting groups), imparting significant resistance to oxidation and photodegradation while minimally impacting the biological activity of the molecules in cellular assays. We propose that incorporating MIDA boronates into the synthetic routes of boronic acid-containing drugs could eliminate costly deprotection and reformulation steps in pharmaceutical development, enabling a more direct route to shelf-stable "MIDA-masked" boronic acid medicines.