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