title: Searching for cyclin-dependent kinase inhibitors using a new variant of the cope elimination.
abstract: beta-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 beta-aminoethylsulfones. When a beta-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.
authors: Northern Institute for Cancer Research, School of Natural Sciences-Chemistry, Bedson Building, University of Newcastle, Newcastle upon Tyne, UK.
authors: Roger J
authors: RJ
authors: Griffin
authors: Andrew
authors: A
authors: Henderson
authors: Nicola J
authors: NJ
authors: Curtin
authors: Aude
authors: A
authors: Echalier
authors: Jane A
authors: JA
authors: Endicott
authors: Ian R
authors: IR
authors: Hardcastle
authors: David R
authors: DR
authors: Newell
authors: Martin E M
authors: ME
authors: Noble
authors: Lan-Zhen
authors: LZ
authors: Wang
authors: Bernard T
authors: BT
authors: Golding