Design of reversible, cysteine-targeted Michael acceptors guided by kinetic and computational analysis.
J Am Chem Soc
; 136(36): 12624-30, 2014 Sep 10.
Article
em En
| MEDLINE
| ID: mdl-25153195
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 ß-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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Acrilonitrila
/
Cisteína
/
Inibidores de Proteínas Quinases
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
J Am Chem Soc
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Estados Unidos