Isoxazolo(aza)naphthoquinones: A new class of cytotoxic Hsp90 inhibitors

Alberto Bargiotti, Loana Musso, Sabrina Dallavalle, Lucio Merlini, Grazia Gallo, Andrea Ciacci, Giuseppe Giannini, Walter Cabri, Sergio Penco, Loredana Vesci, Massimo Castorina, Ferdinando Maria Milazzo, Maria Luisa Cervoni, Marcella Barbarino, Claudio Pisano, Chiara Giommarelli, Valentina Zuco, Michelandrea De Cesare, Franco Zunino

Research output: Contribution to journalArticlepeer-review


A series of 3-aryl-naphtho[2,3-d]isoxazole-4,9-diones and some of their 6-aza analogues were synthesized and found to inhibit the heat shock protein 90 (Hsp90). The compounds were tested for their binding to Hsp90 and for their effects on Hsp90 client proteins expression in a series of human tumour cell lines. Representative compounds (7f, 10c) downregulated the Hsp90 client proteins EGFR, Akt, Cdk4, Raf-1, and survivin, and upregulated Hsp70. Most of the compounds, in particular the alkylated 3-pyridyl derivatives, exhibited potent antiproliferative activity, down to two-digit nanomolar range. Preliminary results indicated in vivo activity of 7f against human epithelial carcinoma A431 model growing as tumour xenograft in nude mice, thus supporting the therapeutic potential of this novel series of Hsp90 inhibitors.

Original languageEnglish
Pages (from-to)64-75
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - Jul 2012


  • Antiproliferative activity
  • Antitumour
  • Hsp90 inhibitors
  • Isoxazolonaphthoquinones
  • QSAR
  • Synthesis

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology


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