Isoxazolo(aza)naphthoquinones: a new class of cytotoxic Hsp90 inhibitors

Eur J Med Chem. 2012 Jul:53:64-75. doi: 10.1016/j.ejmech.2012.03.036.

Alberto Bargiotti ¹, Loana Musso, Sabrina Dallavalle, Lucio Merlini, Grazia Gallo, Andrea Ciacci, Giuseppe Giannini, Walter Cabri, Sergio Penco, Loredana Vesci, Massimo Castorina, Ferdinando Maria Milazzo, Maria Luisa Cervoni, Marcella Barbarino, Claudio Pisano, Chiara Giommarelli, Valentina Zuco, Michelandrea De Cesare, Franco Zunino

Affiliations

Affiliation

1 Dipartimento di Scienze Molecolari Agroalimentari, Università di Milano, Via Celoria 2, 20133 Milano, Italy.

PMID: 22538015 DOI: 10.1016/j.ejmech.2012.03.036

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.

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