Facile synthesis of borofragments and their evaluation in activity-based protein profiling

• Published in: Chemical communications (Cambridge, England) Vol. 51; no. 17; pp. 3608 - 3611
• Main Authors: Adachi, Shinya, Cognetta, Armand B., Niphakis, Micah J., He, Zhi, Zajdlik, Adam, Denis, Jeffrey D. St, Scully, Conor C. G., Cravatt, Benjamin F., Yudin, Andrei K.
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 28.02.2015
• Subjects: Boron Compounds - chemical synthesis; Boron Compounds - chemistry; Boron Compounds - pharmacology; Carboxypeptidases - antagonists & inhibitors; Carboxypeptidases - metabolism; Chemistry; Chemistry, Multidisciplinary; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes; Esterases - antagonists & inhibitors; Esterases - metabolism; Humans; Inhibitors; Modular construction; Molecular Structure; Nucleophiles; Physical Sciences; Profiling; Proteins; Reagents; Science & Technology; Structure-Activity Relationship; Synthesis; BORONIC ACIDS; CROSS-COUPLING REACTIONS; GENERAL-SOLUTION; NATURAL-PRODUCTS; BETA-LACTONE; CHEMISTRY; VERSATILE BUILDING-BLOCK; COMPLEX PROTEOMES; INHIBITORS; SMALL-MOLECULE SYNTHESIS
• ISSN: 1359-7345; 1364-548X
• DOI: 10.1039/c4cc09107h

The discovery of enzyme inhibitors relies on synthetic methods that enable rapid and modular construction of small molecules. Heterocyclic fragments designed to maximize enthalpic interactions with their protein targets represent a particularly desirable class of molecules. Here we describe a reagent that enables straightforward construction of "borofragments'', in which a heterocycle is separated from the boron center by two or three rotatable bonds. The stability of these molecules depends on the MIDA group which likely acts as a slow-release element under biological conditions. Borofragments can be used to discover inhibitors of enzymes that use catalytic oxygen nucleophiles. We have employed this method to identify inhibitors of ABHD10 and the predicted carboxypeptidase CPVL. This technique should be applicable to other classes of targets.