Natural and semisynthetic azaphilones as a new scaffold for Hsp90 inhibitors

• Published in: Bioorganic & medicinal chemistry 2010-08, Vol.18 (16), p.6031-6043
• Main Authors: Musso, Loana, Dallavalle, Sabrina, Merlini, Lucio, Bava, Adriana, Nasini, Gianluca, Penco, Sergio, Giannini, Giuseppe, Giommarelli, Chiara, De Cesare, Andrea, Zuco, Valentina, Vesci, Loredana, Pisano, Claudio, Dal Piaz, Fabrizio, De Tommasi, Nunziatina, Zunino, Franco
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - isolation & purification; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antitumour; Ascomycota - chemistry; Azaphilones; Benzopyrans - chemistry; Benzopyrans - isolation & purification; Benzopyrans - pharmacology; Benzopyrans - therapeutic use; Biological and medical sciences; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Chaperones; Cytotoxicity; Female; General aspects; Hsp90; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - metabolism; Humans; Limited proteolysis; Medical sciences; Mice; Mice, Nude; Natural products; Neoplasms - drug therapy; p53; Pharmacology. Drug treatments; Pigments, Biological - chemistry; Pigments, Biological - isolation & purification; Pigments, Biological - pharmacology; Pigments, Biological - therapeutic use; Plasmon surface resonance
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.06.068

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.