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

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


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
Issue number8
StatePublished - Apr 24 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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