Searching for Cyclin-Dependent Kinase Inhibitors Using a New Variant of the Cope Elimination

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• 作者：Roger J. Griffin ; Andrew Henderson ; Nicola J. Curtin ; Aude Echalier ; Jane A. Endicott ; Ian R. Hardcastle ; David R. Newell ; Martin E. M. Noble ; Lan-Zhen Wang ; and Bernard T. Golding
• 刊名：Journal of the American Chemical Society
• 出版年：2006
• 出版时间：May 10, 2006
• 年：2006
• 卷：128
• 期：18
• 页码：6012 - 6013
• 全文大小：98K
• 年卷期：v.128,no.18(May 10, 2006)
• ISSN：1520-5126

文摘

-Piperidinoethylsulfides are oxidized by m-chloroperbenzoic acid to intermediates containing both N-oxide and sulfone functions. These undergo a Cope-type elimination to a vinylsulfone that can be captured by amines to afford -aminoethylsulfones. When a -aminoethylsulfone group is linked to the 4-position of a phenyl group attached at N-2 of O⁶-cyclohexylmethylguanine, the resulting derivatives are inhibitors of the cyclin-dependent kinase CDK2. One of the most potent inhibitors (IC₅₀ = 45 nM) contained a N-3-hydroxypropyl group on the aminoethylsulfonyl substituent. The crystal structure of this inhibitor bound to CDK2/cyclin A was determined and shows an unusual network of hydrogen bonds. The synthetic methodology developed can be utilized in multiple-parallel format and has numerous potential applications in medicinal chemistry.