Multicomponent mapping of boron chemotypes furnishes selective enzyme inhibitors

Abstract

Heteroatom-rich organoboron compounds have attracted attention as modulators of enzyme function. Driven by the unmet need to develop chemoselective access to boron chemotypes, we report herein the synthesis of α- and β-aminocyano(MIDA)boronates from borylated carbonyl compounds. Activity-based protein profiling of the resulting β-aminoboronic acids furnishes selective and cell-active inhibitors of the (ox)lipid-metabolizing enzyme α/β-hydrolase domain 3 (ABHD3). The most potent compound displays nanomolar in vitro and in situ IC50 values and fully inhibits ABHD3 activity in human cells with no detectable cross-reactivity against other serine hydrolases. These findings demonstrate that synthetic methods that enhance the heteroatom diversity of boron-containing molecules within a limited set of scaffolds accelerate the discovery of chemical probes of human enzymes.

Visible‐Light‐Mediated Decarboxylative Radical Additions to Vinyl Boronic Esters: Rapid Access to γ‐Amino Boronic Esters

“…For example, peptidyl boronic acids can function as inhibitors of serine proteases, an attribute that has led to the commercialization of the antineoplastic drug, bortezomib, for the treatment of relapsed and refractory multiple myeloma (Scheme 1 a) 6. Whilst boronic acid analogues of α‐amino acids are now well established, there have been very few investigations into the use of boron analogues of other biologically important amino acids, such as the neuromodulator γ‐amino butyric acid (GABA) 7, 8, 9. The paucity of such investigations could be due to the lack of availability of these molecules, therefore we decided to address this by developing new methodologies.…”

Solid‐phase synthesis of peptide β‐aminoboronic acids

“…This improved stability has led our group to use β‐aminoboronic acids to bind carbohydrates and catalyze regioselective acylations of sugars . Furthermore, our synthesis of β‐aminoboronic acids have allowed access to low nanomolar inhibitors of hydrolases . Our work demonstrates that the incorporation of boron into heteroatom rich motifs is essential to both synthetic and medicinal avenues.…”

Synthesis of cis‐1,2‐diol‐type chiral ligands and their dioxaborinane derivatives: Application for the asymmetric transfer hydrogenation of various ketones and biological evaluation

“…[29,30] In addition, boron-containing compounds have been explored as inhibitors for different biological targets and some of them were approved by FDA as the drugs to treat a variety of diseases such as multiple myeloma, cancer, etc. [31,32] Because of their biological potential as antibacterial, antioxidant and other agents, three-coordinated dioxaborinane and four-coordinated dioxaborinane complexes containing N ! B dative bonds were found to exhibit significant biological activities.…”