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Multicomponent mapping of boron chemotypes furnishes selective enzyme inhibitors

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 prote...

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Detalles Bibliográficos
Autores principales: Tan, Joanne, Cognetta III, Armand B., Diaz, Diego B., Lum, Kenneth M., Adachi, Shinya, Kundu, Soumajit, Cravatt, Benjamin F., Yudin, Andrei K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701053/
https://www.ncbi.nlm.nih.gov/pubmed/29170371
http://dx.doi.org/10.1038/s41467-017-01319-4
Descripción
Sumario: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 IC(50) 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.