Design, synthesis, and antiproliferative and CDK2-cyclin a inhibitory activity of novel flavopiridol analogues

Yu Mi Ahn, Lakshminarayana Vogeti, Chun Jing Liu, Hari K.R. Santhapuram, Jonathan M. White, Veena Vasandani, Lester A. Mitscher, Gerald H. Lushington, Paul R. Hanson, Douglas R. Powell, Richard H. Himes, Katherine F. Roby, Qizhuang Ye, Gunda I. Georg

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35 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)702-713
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume15
Issue number2
DOIs
StatePublished - Jan 15 2007

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Keywords

  • CDK2-Cyclin A
  • Cytotoxicity
  • Docking simulations
  • Flavopiridol analogues
  • Synthesis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Ahn, Y. M., Vogeti, L., Liu, C. J., Santhapuram, H. K. R., White, J. M., Vasandani, V., Mitscher, L. A., Lushington, G. H., Hanson, P. R., Powell, D. R., Himes, R. H., Roby, K. F., Ye, Q., & Georg, G. I. (2007). Design, synthesis, and antiproliferative and CDK2-cyclin a inhibitory activity of novel flavopiridol analogues. Bioorganic and Medicinal Chemistry, 15(2), 702-713. https://doi.org/10.1016/j.bmc.2006.10.063