title: Natural and semisynthetic azaphilones as a new scaffold for Hsp90 inhibitors.
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.
authors.affiliation: Dipartimento di Scienze Molecolari Agroalimentari, Università di Milano, Via Celoria 2, 20133 Milano, Italy.
authors.forename: Loana
authors.initials: L
authors.lastname: Musso
authors.forename: Sabrina
authors.initials: S
authors.lastname: Dallavalle
authors.forename: Lucio
authors.initials: L
authors.lastname: Merlini
authors.forename: Adriana
authors.initials: A
authors.lastname: Bava
authors.forename: Gianluca
authors.initials: G
authors.lastname: Nasini
authors.forename: Sergio
authors.initials: S
authors.lastname: Penco
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
authors.forename: Chiara
authors.initials: C
authors.lastname: Giommarelli
authors.forename: Andrea
authors.initials: A
authors.lastname: De Cesare
authors.forename: Valentina
authors.initials: V
authors.lastname: Zuco
authors.forename: Loredana
authors.initials: L
authors.lastname: Vesci
authors.forename: Claudio
authors.initials: C
authors.lastname: Pisano
authors.forename: Massimo
authors.initials: M
authors.lastname: Castorina
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Milazzo
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Cervoni
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Dal Piaz
authors.forename: Nunziatina
authors.initials: N
authors.lastname: De Tommasi
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D001203:Ascomycota / Q000737:chemistry*; D001578:Benzopyrans / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy; D010860:Pigments, Biological / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D001578:Benzopyrans; D018841:HSP90 Heat-Shock Proteins; D010860:Pigments, Biological; C494154:azaphilone