The design and synthesis of a small library of 8-amidoflavone, 8-sulfonamidoflavone, 8-amido-7-hydroxyflavone, and heterocyclic analogues of flavopiridol is reported. The potential activity of these compounds as kinase inhibitors was evaluated by cytotoxicity studies in MCF-7 and ID-8 cancer cell lines and inhibition of CDK2-Cyclin A enzyme activity in vitro. The antiproliferative and CDK2-Cyclin A inhibitory activity of these analogues was significantly lower than the activity of flavopiridol. Molecular docking simulations were carried out and these studies suggested a different binding orientation inside the CDK2 binding pocket for these analogues compared to flavopiridol.
Bibliographical noteFunding Information:
This investigation was supported by NIH-COBRE award 1 P20 RR15563 (NIH-NCRR) with matching support from the State of Kansas and the University of Kansas. The authors thank Dr. David Vander Velde and Sarah Neuenswander for the assistance with the NMR measurements, Dr. Todd Williams for HRMS analysis, and Jacquelyn K. Huff for technical assistance. The authors also thank the National Science Foundation (Grant CHE-0079282) and the University of Kansas for funds to purchase the X-ray instrument and computers.
- CDK2-Cyclin A
- Docking simulations
- Flavopiridol analogues