Boronic acid with high oxidative stability and utility in biological contexts

Significance Like thiols, boronic acids are unstable to oxidation in biological contexts, limiting their utility. We discovered that the rate-limiting step in the oxidation of a boronic acid can be slowed by the installation of a pendant carboxyl group that is a ligand to the boron atom. The ensuing boronic acid is 10,000-fold more resistant to oxidation. Experimental and computational analyses reveal that the orientational constraints and electronic effects imposed by the carboxyl group act as intended, slowing the rate-limiting step during oxidation. The new boronic acid retains the useful attributes of simple boronic acids such as forming reversible covalent bonds with saccharides and a protein and could be useful in chemical biology, medicinal chemistry, and allied fields. Despite their desirable attributes, boronic acids have had a minimal impact in biological contexts. A significant problem has been their oxidative instability. At physiological pH, phenylboronic acid and its boronate esters are oxidized by reactive oxygen species at rates comparable to those of thiols. After considering the mechanism and kinetics of the oxidation reaction, we reasoned that diminishing electron density on boron could enhance oxidative stability. We found that a boralactone, in which a carboxyl group serves as an intramolecular ligand for the boron, increases stability by 104-fold. Computational analyses revealed that the resistance to oxidation arises from diminished stabilization of the p orbital of boron that develops in the rate-limiting transition state of the oxidation reaction. Like simple boronic acids and boronate esters, a boralactone binds covalently and reversibly to 1,2-diols such as those in saccharides. The kinetic stability of its complexes is, however, at least 20-fold greater. A boralactone also binds covalently to a serine side chain in a protein. These attributes confer unprecedented utility upon boralactones in the realms of chemical biology and medicinal chemistry.

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