“MIDA masking” of boronic acid therapeutics for enhanced stability and economy
- 1Department of Chemistry, Massachusetts Institute of Technology Cambridge Massachusetts 02139 USA
- 2Department of Biology, Massachusetts Institute of Technology Cambridge Massachusetts 02139 USA
- 3Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology Cambridge Massachusetts 02139 USA
Abstract
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.
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BibTeX
@article{fitzgerald2026mida,
title = {{“MIDA masking” of boronic acid therapeutics for enhanced stability and economy}},
author = {Forrest G. FitzGerald and Jasmin M. Frei and Erika Zhang and Oscar J. Molina and JoLynn B. Giancola and Malo Le Chevalier and Volga Kojasoy and Ronald T. Raines},
journal = {RSC chemical biology},
year = {2026},
month = sep,
doi = {10.1039/d6cb00308g},
url = {https://europepmc.org/article/PMC/PMC13655787},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - “MIDA masking” of boronic acid therapeutics for enhanced stability and economy
AU - Forrest G. FitzGerald
AU - Jasmin M. Frei
AU - Erika Zhang
AU - Oscar J. Molina
AU - JoLynn B. Giancola
AU - Malo Le Chevalier
AU - Volga Kojasoy
AU - Ronald T. Raines
PY - 2026
DA - 2026/09/26
JO - RSC chemical biology
DO - 10.1039/d6cb00308g
UR - https://europepmc.org/article/PMC/PMC13655787
AB - 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.
SN - 2633-0679
ER -