A proximity biotinylation-based approach to identify protein-E3 ligase interactions induced by PROTACs and molecular glues

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

Pulsed light induced trifluoromethylation of 1,3-dimethoxybenzene: A frequency controls chemoselectivity and chemical yield

Herein, we propose a new control method for photochemical reaction with the frequency of the light source as a parameter. Based on this proposal, we have developed a pulsed light induced trifluoromethylation reaction under the simple reaction condition which combined 1,3-dimethoxybenzene/anthraquinone/CF3SO2Na without any other additives, oxidant, and reductant. The yield and regioselectivity were improved and the excess reactions were also suppressed by pulsed light irradiation compared to use of conventional light source. Furthermore, it was found that the reaction yield and chemoselectivity changed with each frequency (length of light ON/OFF time) when only frequency of the pulsed light was varied from 1.4 x 10-5 Hz (a period of 2 h on time and 18 h off time) to 105 Hz (a period of 1µs on time and 9 µs off time) while total irradiation time were fixed at 7200s for all reactions. The result shows that the pulsed light has the potential to control photochemical reactions and that the light irradiation method can be an important factor for the photochemical reaction in addition to conventional factor such as reagents, solution concentration, and temperature

Trifluoromethyl Sulfoxides from Allylic Alcohols and Electrophilic SCF3 Donor by [2,3]-Sigmatropic Rearrangement

International audienc

Enantioselective Benzylation and Allylation of α-Trifluoromethoxy Indanones under Phase-Transfer Catalysis

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)

Trifluoromethyl Sulfoxides from Allylic Alcohols and Electrophilic SCF₃ Donor by [2,3]-Sigmatropic Rearrangement

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

Novel Use of CF3SO2Cl for the Metal-Free Electrophilic Trifluoromethylthiolation

International audienc

Chiral N-Fluorodibenzenesulfonimide Analogues for Enantioselective Electrophilic Fluorination and Oxidative Fluorination

International audienc