Natural and semisynthetic azaphilones as a new scaffold for Hsp90 inhibitors

Loana Musso, Sabrina Dallavalle, Lucio Merlini, Adriana Bava, Gianluca Nasini, Sergio Penco, Giuseppe Giannini, Chiara Giommarelli, Andrea De Cesare, Valentina Zuco, Loredana Vesci, Claudio Pisano, Fabrizio Dal Piaz, Nunziatina De Tommasi, Franco Zunino

Research output: Contribution to journalArticle


A series of mold metabolites of Ascomycetes, structurally belonging to the class of azaphilones, were found to inhibit the heat shock protein Hsp90. In particular, bulgarialactone B was tested for its binding to Hsp90 using surface plasmon resonance and limited proteolysis assays and for its effects on Hsp90 client proteins expression in a series of human tumor cell lines. This compound showed high affinity for Hsp90, interacting with the 90-280 region of the N-terminal domain and down-regulated the Hsp90 client proteins Raf-1, survivin, Cdk4, Akt, and EGFR. Bulgarialactone B and other natural azaphilones showed antiproliferative activity in a panel of human tumor cell lines; their conversion into semisynthetic derivatives by reaction with primary amines increased the antiproliferative activity. Preliminary results indicated in vivo activity of bulgarialactone B against an ascitic ovarian carcinoma xenograft, thus supporting the therapeutic potential of this novel series of Hsp90 inhibitors.

Original languageEnglish
Pages (from-to)6031-6043
Number of pages13
JournalBioorganic and Medicinal Chemistry
Issue number16
Publication statusPublished - Aug 15 2010



  • Antitumour
  • Azaphilones
  • Cancer
  • Chaperones
  • Cytotoxicity
  • Hsp90
  • Limited proteolysis
  • Natural products
  • P53
  • Plasmon surface resonance

ASJC Scopus subject areas

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

Cite this

Musso, L., Dallavalle, S., Merlini, L., Bava, A., Nasini, G., Penco, S., Giannini, G., Giommarelli, C., De Cesare, A., Zuco, V., Vesci, L., Pisano, C., Dal Piaz, F., De Tommasi, N., & Zunino, F. (2010). Natural and semisynthetic azaphilones as a new scaffold for Hsp90 inhibitors. Bioorganic and Medicinal Chemistry, 18(16), 6031-6043.