Natural and semisynthetic azaphilones as a new scaffold for Hsp90 inhibitors.
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.
Musso
Loana
L
Dipartimento di Scienze Molecolari Agroalimentari, Università di Milano, Via Celoria 2, 20133 Milano, Italy.
Dallavalle
Sabrina
S
Merlini
Lucio
L
Bava
Adriana
A
Nasini
Gianluca
G
Penco
Sergio
S
Giannini
Giuseppe
G
Giommarelli
Chiara
C
De Cesare
Andrea
A
Zuco
Valentina
V
Vesci
Loredana
L
Pisano
Claudio
C
Castorina
Massimo
M
Milazzo
Ferdinando
F
Cervoni
Maria Luisa
ML
Dal Piaz
Fabrizio
F
De Tommasi
Nunziatina
N
Zunino
Franco
F
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*
D000970:Antineoplastic Agents; D001578:Benzopyrans; D018841:HSP90 Heat-Shock Proteins; D010860:Pigments, Biological; C494154:azaphilone