Design of Reversible, Cysteine-Targeted Michael Acceptors Guided by Kinetic and Computational Analysis

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• 作者：Shyam Krishnan ; Rand M. Miller ; Boxue Tian ; R. Dyche Mullins ; Matthew P. Jacobson ; Jack Taunton
• 刊名：Journal of the American Chemical Society
• 出版年：2014
• 出版时间：September 10, 2014
• 年：2014
• 卷：136
• 期：36
• 页码：12624-12630
• 全文大小：381K
• ISSN：1520-5126

文摘

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 尾-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.