title: Isoxazolo(aza)naphthoquinones: a new class of cytotoxic Hsp90 inhibitors.
abstract: A series of 3-aryl-naphtho[2,3-d]isoxazole-4,9-diones and some of their 6-aza analogues were synthesized and found to inhibit the heat shock protein 90 (Hsp90). The compounds were tested for their binding to Hsp90 and for their effects on Hsp90 client proteins expression in a series of human tumour cell lines. Representative compounds (7f, 10c) downregulated the Hsp90 client proteins EGFR, Akt, Cdk4, Raf-1, and survivin, and upregulated Hsp70. Most of the compounds, in particular the alkylated 3-pyridyl derivatives, exhibited potent antiproliferative activity, down to two-digit nanomolar range. Preliminary results indicated in vivo activity of 7f against human epithelial carcinoma A431 model growing as tumour xenograft in nude mice, 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: Alberto
authors.initials: A
authors.lastname: Bargiotti
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: Grazia
authors.initials: G
authors.lastname: Gallo
authors.forename: Andrea
authors.initials: A
authors.lastname: Ciacci
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
authors.forename: Walter
authors.initials: W
authors.lastname: Cabri
authors.forename: Sergio
authors.initials: S
authors.lastname: Penco
authors.forename: Loredana
authors.initials: L
authors.lastname: Vesci
authors.forename: Massimo
authors.initials: M
authors.lastname: Castorina
authors.forename: Ferdinando Maria
authors.initials: FM
authors.lastname: Milazzo
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Cervoni
authors.forename: Marcella
authors.initials: M
authors.lastname: Barbarino
authors.forename: Claudio
authors.initials: C
authors.lastname: Pisano
authors.forename: Chiara
authors.initials: C
authors.lastname: Giommarelli
authors.forename: Valentina
authors.initials: V
authors.lastname: Zuco
authors.forename: Michelandrea
authors.initials: M
authors.lastname: De Cesare
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000737:chemistry*; D051379:Mice; D008958:Models, Molecular; D009285:Naphthoquinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D009285:Naphthoquinones