Boronic acid

Not to be confused with boric acid or borinic acid.

The general structure of a boronic acid, where R is a substituent.

A boronic acid is an organic compound related to boric acid (B(OH)3) in which one of the three hydroxyl groups (−OH) is replaced by an alkyl or aryl group (represented by R in the general formula R−B(OH)2).[1] As a compound containing a carbon–boron bond, members of this class thus belong to the larger class of organoboranes.

Boronic acids act as Lewis acids. Their unique feature is that they are capable of forming reversible covalent complexes with sugars, amino acids, hydroxamic acids, etc. (molecules with vicinal, (1,2) or occasionally (1,3) substituted Lewis base donors (alcohol, amine, carboxylate)). The pKa of a boronic acid is ~9, but they can form tetrahedral boronate complexes with pKa ~7. They are occasionally used in the area of molecular recognition to bind to saccharides for fluorescent detection or selective transport of saccharides across membranes.

Boronic acids are used extensively in organic chemistry as chemical building blocks and intermediates predominantly in the Suzuki coupling. A key concept in its chemistry is transmetallation of its organic residue to a transition metal.

The compound bortezomib with a boronic acid group is a drug used in chemotherapy. The boron atom in this molecule is a key substructure because through it certain proteasomes are blocked that would otherwise degrade proteins. Boronic acids are known to bind to active site serines and are part of inhibitors for porcine pancreatic lipase,[2] subtilisin[3] and the protease Kex2.[4] Furthermore, boronic acid derivatives constitute a class of inhibitors for human acyl-protein thioesterase 1 and 2, which are cancer drug targets within the Ras cycle.[5]

The boronic acid functional group is reputed to have low inherent toxicity. This is one of the reasons for the popularity of the Suzuki coupling in the development and synthesis of pharmaceutical agents. However, a significant fraction of commonly used boronic acids and their derivatives were recently found to gives a positive Ames test and act as chemical mutagens. The mechanism of mutagenicity is thought to involve the generation of organic radicals via oxidation of the boronic acid by atmospheric oxygen.[6]

  1. ^ IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version: (2006–) "Boronic Acids". doi:10.1351/goldbook.B00714
  2. ^ Garner, C. W. (10 June 1980). "Boronic acid inhibitors of porcine pancreatic lipase". The Journal of Biological Chemistry. 255 (11): 5064–5068. doi:10.1016/S0021-9258(19)70749-2. ISSN 0021-9258. PMID 7372625.
  3. ^ Lindquist, R. N.; Terry, C. (January 1974). "Inhibition of subtilisin by boronic acids, potential analogs of tetrahedral reaction intermediates". Archives of Biochemistry and Biophysics. 160 (1): 135–144. doi:10.1016/s0003-9861(74)80018-4. ISSN 0003-9861. PMID 4364061.
  4. ^ Holyoak, Todd; Wilson, Mark A.; Fenn, Timothy D.; Kettner, Charles A.; Petsko, Gregory A.; Fuller, Robert S.; Ringe, Dagmar (10 June 2003). "2.4 A resolution crystal structure of the prototypical hormone-processing protease Kex2 in complex with an Ala-Lys-Arg boronic acid inhibitor". Biochemistry. 42 (22): 6709–6718. doi:10.1021/bi034434t. ISSN 0006-2960. PMID 12779325.
  5. ^ Zimmermann, Tobias J.; Bürger, Marco; Tashiro, Etsu; Kondoh, Yasumitsu; Martinez, Nancy E.; Görmer, Kristina; Rosin-Steiner, Sigrid; Shimizu, Takeshi; Ozaki, Shoichiro (2 January 2013). "Boron-based inhibitors of acyl protein thioesterases 1 and 2". ChemBioChem. 14 (1): 115–122. doi:10.1002/cbic.201200571. ISSN 1439-7633. PMID 23239555. S2CID 205557212.
  6. ^ Hansen, Marvin M.; Jolly, Robert A.; Linder, Ryan J. (29 July 2015). "Boronic Acids and Derivatives—Probing the Structure–Activity Relationships for Mutagenicity". Organic Process Research & Development. 19 (11): 1507–1516. doi:10.1021/acs.oprd.5b00150. ISSN 1083-6160.