RESUMEN
Proteolysis-targeting chimaeras (PROTACs) as well as molecular glues such as immunomodulatory drugs (IMiDs) and indisulam are drugs that induce interactions between substrate proteins and an E3 ubiquitin ligases for targeted protein degradation. Here, we develop a workflow based on proximity-dependent biotinylation by AirID to identify drug-induced neo-substrates of the E3 ligase cereblon (CRBN). Using AirID-CRBN, we detect IMiD-dependent biotinylation of CRBN neo-substrates in vitro and identify biotinylated peptides of well-known neo-substrates by mass spectrometry with high specificity and selectivity. Additional analyses reveal ZMYM2 and ZMYM2-FGFR1 fusion protein-responsible for the 8p11 syndrome involved in acute myeloid leukaemia-as CRBN neo-substrates. Furthermore, AirID-DCAF15 and AirID-CRBN biotinylate neo-substrates targeted by indisulam and PROTACs, respectively, suggesting that this approach has the potential to serve as a general strategy for characterizing drug-inducible protein-protein interactions in cells.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Bioensayo , Proteínas de Unión al ADN/genética , Hepatocitos/metabolismo , Linfocitos/metabolismo , Factores de Transcripción/genética , Ubiquitina-Proteína Ligasas/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Biotinilación , Línea Celular Tumoral , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica , Células HEK293 , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Humanos , Factores Inmunológicos/farmacología , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Linfocitos/citología , Linfocitos/efectos de los fármacos , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Unión Proteica , Mapeo de Interacción de Proteínas , Proteolisis/efectos de los fármacos , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Especificidad por Sustrato , Sulfonamidas/farmacología , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
The organo-catalyzed enantioselective benzylation reaction of α-trifluoromethoxy indanones afforded α-benzyl-α-trifluoromethoxy indanones with a tetrasubstituted stereogenic carbon center in excellent yield with moderate enantioselectivity (up to 57% ee). Cinchona alkaloid-based chiral phase transfer catalysts were found to be effective for this transformation, and both enantiomers of α-benzyl-α-trifluoromethoxy indanones were accessed, depended on the use of cinchonidine and cinchonine-derived catalyst. The method was extended to the enantioselective allylation reaction of α-trifluoromethoxy indanones to give the allylation products in moderate yield with good enantioselectivity (up to 76% ee).
Asunto(s)
Derivados de Alilbenceno/química , Fluoruros/química , Indanos/química , Catálisis , Alcaloides de Cinchona/química , Estructura Molecular , EstereoisomerismoRESUMEN
The synthesis of chiral, nonracemic difluoromethylthio (SCF2H) compounds that contain a tetrasubstituted stereogenic center is reported. Racemic α-SCF2H-ß-ketoallylesters 5 were initially prepared by an electrophilic difluoromethylthiolation of ß-ketoallylesters 6, followed by a Pd-catalyzed Tsuji decarboxylative asymmetric allylic alkylation (DAAA) to provide a wide variety of chiral, nonracemic α-allyl-α-SCF2H-ketones (4) with high enantiopurity. This strategy can be extended to the enantioselective synthesis of chiral, nonracemic α-allyl-α-trifluoromethylthio(SCF3)-ketones (7).
RESUMEN
The palladium-catalyzed asymmetric decarboxylative allylic alkylation of trifluoromethoxy allyl enol carbonates afforded enantioenriched α-trifluoromethoxy allyl ketones that feature a tetrasubstituted α-stereogenic center in excellent yield and high enantioselectivity. The method was further extended to the asymmetric synthesis of α-difluoromethoxy and α-methoxy allyl ketones, which proceeded under similar catalytic conditions.
RESUMEN
The regioselective trifluoromethylthiolation of indole derivatives was achieved under reductive conditions with trifluoromethanesulfonyl chloride as the readily available source of electrophilic SCF3 and a phosphine as the reducing agent. It is a straightforward process free from any metal and also applicable for the trifluoromethylthiolation of other azaarenes, enamines, and enoxysilanes.
RESUMEN
Enantiomerization of allylic trifluoromethyl sulfoxides occurs spontaneously at room temperature through the corresponding allylic trifluoromethanesulfenates via a [2,3]-sigmatropic rearrangement. Dynamic enantioselective high-performance liquid chromatography (HPLC) analysis revealed the stereodynamics of these sulfoxides ranging from chromatographic resolution to peak coalescence at temperatures between 5 and 53 °C. The rate constant of enantiomerization and activation parameters were determined and compared with Density Functional Theory (DFT) calculations.
Asunto(s)
Hidrocarburos Fluorados/química , Cromatografía Líquida de Alta Presión/métodos , Teoría Cuántica , Estereoisomerismo , Sulfóxidos/químicaRESUMEN
An electrophilic trifluoromethylthiolation of allylic alcohols produces the corresponding allylic trifluoromethanesulfenates, which spontaneously rearrange into trifluoromethyl sulfoxides via a [2,3]-sigmatropic rearrangement. The reaction is straightforward and proceeds in good to high yields for the preparation of various allylic trifluoromethyl sulfoxides.
Asunto(s)
Hidrocarburos Fluorados/síntesis química , Propanoles/química , Sulfóxidos/síntesis química , Hidrocarburos Fluorados/química , Estructura Molecular , Sulfóxidos/químicaRESUMEN
We report on the self-disproportionation of enantiomers (SDE) of non-racemic thalidomide (1) and 3'-fluorothalidomide (2) under the conditions of gravity-driven achiral silica-gel chromatography. The presence of a fluorine atom on the chiral center dramatically alters the structure and polarity of 1 and 2, resulting in the opposite SDE profile on silica-gel.