RESUMEN
The compatibility of free boronic acid building blocks in multicomponent reactions to readily create large libraries of diverse and complex small molecules was investigated. Traditionally, boronic acid synthesis is sequential, synthetically demanding, and time-consuming, which leads to high target synthesis times and low coverage of the boronic acid chemical space. We have performed the synthesis of large libraries of boronic acid derivatives based on multiple chemistries and building blocks using acoustic dispensing technology. The synthesis was performed on a nanomole scale with high synthesis success rates. The discovery of a protease inhibitor underscores the usefulness of the approach. Our acoustic dispensing-enabled chemistry paves the way to highly accelerated synthesis and miniaturized reaction scouting, allowing access to unprecedented boronic acid libraries.
Asunto(s)
Ácidos Borónicos/química , Estructura Molecular , Bibliotecas de Moléculas Pequeñas/química , Ácidos Borónicos/síntesis química , Ácidos Borónicos/clasificación , Cianuros/síntesis química , Cianuros/química , Espectrometría de Masas/métodos , Microondas , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/clasificaciónRESUMEN
Proteasome inhibition is a validated therapeutic strategy for the treatment of B-cell neoplasms. The peptide boronate based inhibitor bortezomib has become an important tool in the armamentarium for the treatment of multiple myeloma (MM) and has spurred the development of new agents that target the catalytic activities of the proteasome. Five of these agents, representing three distinct chemical classes, have reached clinical testing. These compounds have properties similar to and distinct from bortezomib. Here, the preclinical activity and clinical development of these agents are reviewed with special attention given to comparisons with bortezomib.