Discovery of Quinolinediones Exhibiting a Heat Shock Response and Angiogenesis Inhibition

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• 作者：Robert H. J. Hargreaves ; Cynthia L. David ; Luke J. Whitesell ; Daniel V. LaBarbera ; Akmal Jamil ; Jean C. Chapuis ; Edward B. Skibo
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：April 24, 2008
• 年：2008
• 卷：51
• 期：8
• 页码：2492 - 2501
• 全文大小：1290K
• 年卷期：v.51,no.8(April 24, 2008)
• ISSN：1520-4804

文摘

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-biphenylquinoline-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 quinoline-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.