Imidazo[2,1 -b]thiazolylmethylene- and indolylmethylene-2-indolinones: a new class of cyclin-dependent kinase inhibitors. Design, synthesis, and CDK1/cyclin B inhibition.
Compounds containing a 2-indolinone moiety linked to imidazothiazole and indole fragments were studied as cyclin-dependent kinase inhibitors. The activity of all the new derivatives was tested in vitro against CDK1/cyclinB and the selectivity towards two other kinases was determined for the most promising compounds. The binding mode of one representative compound was investigated by means of a three-dimensional model of the inhibitor-CDK1 complex. The work allowed us to identify (2-chloroindolyl)methylene-2-indolinone as a new lead of a class of CDK1/cyclinB inhibitors, whose potency can be improved by the introduction of suitable variations on the basic molecular skeleton.
Andreani
A
A
Dipartimento di Scienze Farmaceutiche, Università di Bologna, Italy. aldoandr@alma.unibo.it
Cavalli
A
A
Granaiola
M
M
Leoni
A
A
Locatelli
A
A
Morigi
R
R
Rambaldi
M
M
Recanatini
M
M
Garnier
M
M
Meijer
L
L
D001665:Binding Sites; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D019926:Cyclin B / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular
D019926:Cyclin B; D004791:Enzyme Inhibitors; D007211:Indoles; D016203:CDC2 Protein Kinase