Thio- and oxoflavopiridols, cyclin-dependent kinase 1-selective inhibitors: Synthesis and biological effects

Flavopiridol analogues, thio- and oxoflavopiridols which contain a sulfur ( 16) or oxygen (18) atom linker between a chromone ring and the hydrophobic side chain, are selective cyclin-dependent kinase 1 (CDK1) inhibitors with an IC50 Of 110 and 130 nM. These analogues were prepared from key intermedi ate 7 by substituting the ethyl sulfoxide. Enantio pure intermediate piperi done 10 was obtained from the racemic piperidone 8 via a very efficient "dy namic kinetic resolution" in 76% yield. Hydrophobic side chains such as chl orophenyl or tert-butyl produced potent CDK1 inhibitory activity, while hyd rophilic side chains such as pyrimidine or aniline caused a severe reductio n in CDK inhibitory activity. These analogues are competitive inhibitors wi th respect to ATP, and therefore activity was dependent upon the CDK subuni t without being affected by the cyclin subunit or protein substrate. Thio- and oxoflavopiridols 16 and 18 are not only selective within the CDK family but also discriminated between unrelated serine/threonine and tyrosine pro tein kinases. CDK1 selective thio- and oxoflavopiridol analogues inhibit th e colony-forming ability of multiple human tumor cell lines and possess a u nique antiproliferative profile in comparison to flavopiridol.