Searching for cyclin-dependent kinase inhibitors using a new variant of the cope elimination |
| |
Authors: | Griffin Roger J Henderson Andrew Curtin Nicola J Echalier Aude Endicott Jane A Hardcastle Ian R Newell David R Noble Martin E M Wang Lan-Zhen Golding Bernard T |
| |
Affiliation: | Northern Institute for Cancer Research, School of Natural Sciences-Chemistry, Bedson Building, University of Newcastle, Newcastle upon Tyne, UK. |
| |
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. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|