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

被引:38
作者
Baruchello, Riccardo [1 ]
Simoni, Daniele [1 ]
Grisolia, Giuseppina [1 ]
Barbato, Giuseppina [1 ]
Marchetti, Paolo [1 ]
Rondanin, Riccardo [1 ]
Mangiola, Stefania [1 ]
Giannini, Giuseppe [2 ]
Brunetti, Tiziana [2 ]
Alloatti, Domenico [2 ]
Gallo, Grazia [2 ]
Ciacci, Andrea [2 ]
Vesci, Loredana [2 ]
Castorina, Massimo [2 ]
Milazzo, Ferdinando M. [2 ]
Cervoni, Maria L. [2 ]
Guglielmi, Mario B. [2 ]
Barbarino, Marcella [2 ]
Fodera, Rosanna [2 ]
Pisano, Claudio [2 ]
Cabri, Walter [2 ]
机构
[1] Univ Ferrara, Dipartimento Sci Farmaceut, I-44121 Ferrara, Italy
[2] R&D Sigma Tau Ind Farmaceut Riunite SpA, I-00040 Pomezia, Roma, Italy
关键词
HSP90 MOLECULAR CHAPERONE; HEAT-SHOCK-PROTEIN-90; INHIBITORS; DRUG DESIGN; CANCER; IDENTIFICATION; GELDANAMYCIN; DISCOVERY; TRANSFORMATION; COMPLEX; TARGET;
D O I
10.1021/jm201155e
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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,S-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 heteroarylarnides, 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.
引用
收藏
页码:8592 / 8604
页数:13
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