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Isoxazolo(aza)naphthoquinones: A new class of cytotoxic Hsp90 inhibitors
Ist Teil von
European journal of medicinal chemistry, 2012-07, Vol.53, p.64-75
Ort / Verlag
Kidlington: Elsevier Masson SAS
Erscheinungsjahr
2012
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
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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► A series of 3-aryl-naphtho[2,3–d]isoxazole-4,9-diones and some of their 6-aza analogues were synthesized. ► The compounds were tested for their binding to Hsp90 and for their effects on Hsp90 client proteins expression. ► Most of the compounds exhibited potent antiproliferative activity. ► The in vivo activity of a representative compound was evaluated.