Discovery of quinolinediones exhibiting a heat shock response and angiogenesis inhibition

Robert H.J. Hargreaves, Cynthia L. David, Luke J. Whitesell, Daniel V. LaBarbera, Akmal Jamil, Jean Chapuis, Edward B. Skibo

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13 Scopus citations

Abstract

A series of substituted quinoline-5,8-diones were synthesized and evaluated as inhibitors of the chaperone protein Hsp90 using two assays: competition for binding to C-terminal ATP-binding site and competition for binding to N-terminal ATP-binding site. In addition, the ability of the compounds to induce the heat shock response was determined using a reporter fibroblast cell line. Of all the compounds assayed, only 6-aziridinyl-2-biphenylquinolinc-5,8-dione induced a heat shock response and did so without interacting at the ATP binding sites of Hsp90. COMPARE analysis was carried out on quinolinc-5,8-diones active in the National Cancer Institute's 60-cell line screen with the goal of discovering quinoline-5,8-dione structures that interact with other cellular targets (molecular targets) important for cancer chemotherapy. COMPARE analysis led to the discovery of a combretastatin-like quinoline-5,8-dione structure that, in fact, inhibited angiogenesis.

Original languageEnglish (US)
Pages (from-to)2492-2501
Number of pages10
JournalJournal of Medicinal Chemistry
Volume51
Issue number8
DOIs
StatePublished - Apr 24 2008

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Hargreaves, R. H. J., David, C. L., Whitesell, L. J., LaBarbera, D. V., Jamil, A., Chapuis, J., & Skibo, E. B. (2008). Discovery of quinolinediones exhibiting a heat shock response and angiogenesis inhibition. Journal of Medicinal Chemistry, 51(8), 2492-2501. https://doi.org/10.1021/jm7014099