Design of Reversible, Cysteine-Targeted Michael Acceptors Guided by Kinetic and Computational Analysis
Citations Over TimeTop 10% of 2014 papers
Abstract
Electrophilic probes that covalently modify a cysteine thiol often show enhanced pharmacological potency and selectivity. Although reversible Michael acceptors have been reported, the structural requirements for reversibility are poorly understood. Here, we report a novel class of acrylonitrile-based Michael acceptors, activated by aryl or heteroaryl electron-withdrawing groups. We demonstrate that thiol adducts of these acrylonitriles undergo β-elimination at rates that span more than 3 orders of magnitude. These rates correlate inversely with the computed proton affinity of the corresponding carbanions, enabling the intrinsic reversibility of the thiol-Michael reaction to be tuned in a predictable manner. We apply these principles to the design of new reversible covalent kinase inhibitors with improved properties. A cocrystal structure of one such inhibitor reveals specific noncovalent interactions between the 1,2,4-triazole activating group and the kinase. Our experimental and computational study enables the design of new Michael acceptors, expanding the palette of reversible, cysteine-targeted electrophiles.
Related Papers
- → Regioselection in the reaction of α-silyloxyallyl carbanions with electrrophiles(1979)25 cited
- → Delocalized Carbanions in Synthesis(1991)23 cited
- → C,C-coupling with sulfur-stabilized carbanions - 7. Diastereoselectivity in the addition of electrophiles to the carbanions of 2-(alkylthio)thiolane 1-oxides(1997)8 cited
- → Products from metallation and attempted metallation of 1-alkyl-4,6-diphenyl-2-pyridones and subsequent reaction with electrophiles(1980)7 cited
- → Stereoselective Addition of Sulfur-Stabilized Carbanions(1994)