In Situ Observation of Thiol Michael Addition to a Reversible Covalent Drug in a Crystalline Sponge. Issue 16 (11th March 2016)

• Record Type: Journal Article
• Authors: Duplan, Vincent; Hoshino, Manabu; Li, Wei; Honda, Tadashi; Fujita, Makoto
• Is Part Of: Angewandte Chemie international edition. Volume 55:Issue 16(2016)
• Page Start: 4919
• Page End: 4923
• Publication Date: 2016-03-11
• Subjects: chemical equilibrium -- crystalline sponge -- Michael addition -- reversible covalent inhibitors -- structure elucidation; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201509801
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: A reversible Michael addition reaction between thiol nucleophiles and cyanoenones has been previously postulated to be the mechanism‐of‐action of a new family of reversible covalent drugs. However, the hypothetical Michael adducts in this mechanism have only been detected by spectroscopic methods in solution. Herein, the crystallographic observation of reversible Michael addition with a potent cyanoenone drug candidate by means of the crystalline‐sponge method is reported. After inclusion of the cyanoenone substrate, the sponge crystal was treated with a thiol solution. Subsequent crystallographic analysis confirmed the single‐crystal‐to‐single‐crystal transformation of the substrate into the impermanent Michael adduct. Abstract : Seeing is believing : The formation of a cyanoenone Michael adduct, postulated to be involved in the mechanism‐of‐action of a new family of reversible covalent drugs, was crystallographically observed in situ in the pore of a crystalline sponge. The reaction was performed by treatment of the crystalline sponge first with the substrate followed by the thiol‐based reagent of interest.