ABSTRACT
This paper describes a tunable and stereoselective dual catalytic system that uses copper and palladium reagents. This cooperative silylcupration and palladium-catalyzed allylation readily affords trisubstituted alkenylsilanes. Fine-tuning the reaction conditions allows selective access to one stereoisomer over the other. This new methodology tolerates different substituents on both coupling partners with high levels of stereoselectivity. The one-pot reaction involving a Cu(I)/Pd(0) cooperative dual catalyst directly addresses the need to develop more time-efficient and less-wasteful synthetic pathways.
ABSTRACT
Deubiquitinating enzymes (DUBs) are a growing target class across multiple disease states, with several inhibitors now reported. b-AP15 and VLX1570 are two structurally related USP14/UCH-37 inhibitors. Through a proteomic approach, we demonstrate that these compounds target a diverse range of proteins, resulting in the formation of higher molecular weight (MW) complexes. Activity-based proteome profiling identified CIAPIN1 as a submicromolar covalent target of VLX1570, and further analysis demonstrated that high MW complex formation leads to aggregation of CIAPIN1 in intact cells. Our results suggest that in addition to DUB inhibition, these compounds induce nonspecific protein aggregation, providing molecular explanation for general cellular toxicity.
Subject(s)
Azepines/pharmacology , Benzylidene Compounds/pharmacology , Deubiquitinating Enzymes/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Piperidones/pharmacology , Protein Multimerization/drug effects , Azepines/chemistry , Benzylidene Compounds/chemistry , Cell Line, Tumor , Cross-Linking Reagents/chemistry , Cross-Linking Reagents/pharmacology , Deubiquitinating Enzymes/chemistry , Enzyme Inhibitors/chemistry , Humans , Intracellular Signaling Peptides and Proteins/chemistry , Intracellular Signaling Peptides and Proteins/metabolism , Piperidones/chemistry , Proteome/chemistry , Proteome/metabolism , ProteomicsABSTRACT
Enynes are versatile building blocks in organic synthesis. A copper-catalyzed Hiyama-type cross-coupling of vinylsiloxanes with bromoalkynes is presented. This mild and efficient method led to the formation of various sensitive enynes. The use of cis, trans, and 1,1'-disubstituted vinylsiloxanes was allowed, and full retention of stereochemistry was observed. Sensitive groups such as halides, unsaturated ketones, and aldehydes were fully tolerated.