Several inhibitors of cyclin-dependent kinases (CDKs), including the 2,6,9-trisubstituted purine derivative roscovitine, are currently being evaluated in clinical trials as potential anticancer drugs. Here, we describe a new series of roscovitine derivatives that show increased potency in vitro. The series was tested for cytotoxicity against six cancer cell lines and for inhibition of CDKs. For series bearing 2-(hydroxyalkylamino) moiety, cytotoxic potency strongly correlated with anti-CDK2 activity. Importantly, structural changes that increase biochemical and anticancer activities of these compounds also increase elimination half-life. The most potent compounds were investigated further to assess their ability to influence cell cycle progression, p53-regulated transcription and apoptosis. All the observed biological effects were consistent with inhibition of CDKs involved in the regulation of cell cycle and transcription.
- MeSH
- Apoptosis drug effects MeSH
- K562 Cells MeSH
- Cyclin-Dependent Kinases antagonists & inhibitors metabolism MeSH
- HCT116 Cells MeSH
- Protein Kinase Inhibitors chemical synthesis chemistry pharmacology MeSH
- Humans MeSH
- Models, Molecular MeSH
- Molecular Structure MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents chemical synthesis chemistry pharmacology MeSH
- Purines chemical synthesis chemistry pharmacology MeSH
- Drug Screening Assays, Antitumor MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
