title: In Situ Observation of Thiol Michael Addition to a Reversible Covalent Drug in a Crystalline Sponge.
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.
authors.affiliation: Department of Applied Chemistry, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.
authors.forename: Vincent
authors.initials: V
authors.lastname: Duplan
authors.affiliation: Department of Applied Chemistry, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Hoshino
authors.affiliation: Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY, 11794, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY, 11794, USA.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Honda
authors.affiliation: Department of Applied Chemistry, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan. mfujita@appchem.t.u-tokyo.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Fujita
mesh_terms: D003460:Crystallization; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared; D013438:Sulfhydryl Compounds / Q000737:chemistry*
chemical_list: D004364:Pharmaceutical Preparations; D013438:Sulfhydryl Compounds
keywords: Michael addition; chemical equilibrium; crystalline sponge; reversible covalent inhibitors; structure elucidation