Natural and semisynthetic azaphilones as a new scaffold for Hsp90 inhibitors

  • Bioorg Med Chem. 2010 Aug 15;18(16):6031-43. doi: 10.1016/j.bmc.2010.06.068.
Loana Musso  1 ,  Sabrina Dallavalle ,  Lucio Merlini ,  Adriana Bava ,  Gianluca Nasini ,  Sergio Penco ,  Giuseppe Giannini ,  Chiara Giommarelli ,  Andrea De Cesare ,  Valentina Zuco ,  Loredana Vesci ,  Claudio Pisano ,  Massimo Castorina ,  Ferdinando Milazzo ,  Maria Luisa Cervoni ,  Fabrizio Dal Piaz ,  Nunziatina De Tommasi ,  Franco Zunino
Affiliations
  • 1. Dipartimento di Scienze Molecolari Agroalimentari, Università di Milano, Via Celoria 2, 20133 Milano, Italy.
PMID: 20655237 DOI: 10.1016/j.bmc.2010.06.068
Abstract

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.