Novel 3,4-Isoxazolediamides as Potent Inhibitors of Chaperone Heat Shock Protein 90

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• 作者：Riccardo Baruchello ; Daniele Simoni ; Giuseppina Grisolia ; Giuseppina Barbato ; Paolo Marchetti ; Riccardo Rondanin ; Stefania Mangiola ; Giuseppe Giannini ; Tiziana Brunetti ; Domenico Alloatti ; Grazia Gallo ; Andrea Ciacci ; Loredana Vesci ; Massimo Castorina ; Ferdinando M. Milazzo ; Maria L. Cervoni ; Mario B. Guglielmi ; Marcella Barbarino ; Rosanna Foder脿 ; Claudio Pisano ; Walter Cabri
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：December 22, 2011
• 年：2011
• 卷：54
• 期：24
• 页码：8592-8604
• 全文大小：620K
• 年卷期：v.54,no.24(December 22, 2011)
• ISSN：1520-4804

文摘

A structural investigation on the isoxazole scaffold led to the discovery of 3,4-isoxazolediamide compounds endowed with potent Hsp90 inhibitory properties. We have found that compounds possessing a nitrogen atom directly attached to the C-4 heterocycle ring possess in vitro Hsp90 inhibitory properties at least comparable to those of the structurally related 4,5-diarylisoxazole derivatives. A group of compounds from this series of diamides combine potent binding affinity and cell growth inhibitory activity in both series of alkyl- and aryl- or heteroarylamides, with IC₅₀ in the low nanomolar range. The 3,4-isoxazolediamides were also very effective in causing dramatic depletion of the examined client proteins and, as expected for the Hsp90 inhibitors, always induced a very strong increase in the expression levels of the chaperone Hsp70. In vivo studies against human epidermoid carcinoma A431 showed an antitumor effect of morpholine derivative 73 comparable to that induced by the reference compound 10.