Discovery of a Covalent Inhibitor of Pro-Caspase-1 Zymogen Blocking NLRP3 Inflammasome Activation and Pyroptosis.

Caspase-1 plays a central role in innate immunity, as its activation by inflammasomes induces the production of proinflammatory cytokines and pyroptosis. However, specific inhibition of the enzymatic activity of this protease is not effective in suppressing inflammation, owing to its enzyme-independent function. Herein, we identified a cyclohexenyl isothiocyanate compound (CIB-1476) that potently inhibited caspase-1 activity and suppressed the assembly and activation of the NLRP3 inflammasome and gasdermin-D-mediated pyroptosis. Mechanistically, CIB-1476 directly targeted pro-caspase-1 as an irreversible covalent inhibitor by binding to Cys285 and Cys397, resulting in more durable anti-inflammatory effects in the suppression of enzyme-dependent IL-1ß production and enzyme-independent nuclear factor κB activation. Chemoproteomic profiling demonstrated the engagement of CIB-1476 with caspase-1. CIB-1476 showed potent therapeutic effects by suppressing inflammasome activation in mice, which was abolished in Casp1-/- mice. These results warrant further development of CIB-1476 along with its analogues as a novel strategy for caspase-1 inhibitors.

Concise synthesis of chiral γ-butenolides via an allylation/lactonization cascade reaction.

A highly enantioselective allylation/lactonization cascade was developed, which provides a concise and efficient route to chiral γ-butenolides under mild conditions. Most of the reaction examples can be completed in 10 minutes with high selectivity.

Enantioselective Synthesis of Spiro[cyclopentane-1,3'-oxindole] Scaffolds with Five Consecutive Stereocenters.

A highly diastereo- and enantioselective cascade annulation reaction of Morita-Baylis-Hillman (MBH) maleimides of isatins with ortho-hydroxychalcones was achieved by a chiral N,N'-dioxide/Mg(II) complex Lewis acid catalyst. This strategy provides a concise and efficient route to densely functionalized spiro[cyclopentane-1,3'-oxindole] compounds with five consecutive stereocenters. The reaction itself features mild conditions, good functional group compatibility, and broad substrate scope (62 examples, up to 99% yield, up to >20:1 dr, 97% ee). In addition, an obvious ligand acceleration effect and chiral amplification effect were observed. DFT calculations were performed to elucidate the stereoselectivity observed. The gram-scale synthesis and the inhibitory effect of two products on the viability of A549 cells demonstrate the potential utility of the current method.

Iron-Catalyzed Asymmetric Imidation of Sulfides via Sterically Biased Nitrene Transfer.

Transition-metal-catalyzed enantioselective nitrene transfer to sulfides has emerged as one of the most powerful strategies for rapid construction of enantioenriched sulfimides. However, achieving stereocontrol over highly active earth-abundant transition-metal nitrenoid intermediates remains a formidable challenge compared with precious metals. Herein, we disclose a chiral iron(II)/N,N'-dioxide-catalyzed enantioselective imidation of dialkyl and alkyl aryl sulfides using iminoiodinanes as nitrene precursors. A series of chiral sulfimides were obtained in moderate-to-good yields with high enantioselectivities (56 examples, up to 99% yield, 98:2 e.r.). The utility of this methodology was demonstrated by late-stage modification of complex molecules and synthesis of the chiral insecticide sulfoxaflor and the intermediates of related bioactive compounds. Based on experimental studies and theoretical calculations, a water-bonded high-spin iron nitrenoid species was identified as the key intermediate. The observed stereoselectivity was original from the steric repulsion between the amide unit of the ligand in the chiral cave and the bulky substituent of sulfides. Additionally, dioxazolones proved to be suitable acylnitrene precursors in the presence of an iron(III)/N,N'-dioxide complex, resulting in the formation of enantioselectivity-reversed sulfimides (14 examples, up to 81% yield, 97:3 e.r.).

The Effect of Basic Ligands and Alkenes on the Regioselectivity of C-H Additions of Tertiary Amines to Alkenes.

Highly regioselective C-H alkylation reactions of tertiary anilines and tertiary alkyl amines with simple alkenes have been achieved by the use of imidazolin-2-iminato scandium alkyl complexes. This protocol provided an efficient and atom-economical route to structurally diverse tertiary amine derivatives. The basic ligand, a coordinating THF in the catalyst and the substitution of alkene substrates were found to switch the regioselectivity of the C-H alkylation reactions of tertiary anilines presumably due to the generation of different types of catalytically active species or the formation of relatively stable intermediates. On the basis of the deuterium labeling experiments and KIE experiments, possible catalytical cycles were provided to understand the reaction mechanism as well as the regioselectivity.