title: Novel 3,4-isoxazolediamides as potent inhibitors of chaperone heat shock protein 90.
abstract: 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.
authors: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Ferrara, I-44121 Ferrara, Italy.
authors: Riccardo
authors: R
authors: Baruchello
authors: Daniele
authors: D
authors: Simoni
authors: Giuseppina
authors: G
authors: Grisolia
authors: Giuseppina
authors: G
authors: Barbato
authors: Paolo
authors: P
authors: Marchetti
authors: Riccardo
authors: R
authors: Rondanin
authors: Stefania
authors: S
authors: Mangiola
authors: Giuseppe
authors: G
authors: Giannini
authors: Tiziana
authors: T
authors: Brunetti
authors: Domenico
authors: D
authors: Alloatti
authors: Grazia
authors: G
authors: Gallo
authors: Andrea
authors: A
authors: Ciacci
authors: Loredana
authors: L
authors: Vesci
authors: Massimo
authors: M
authors: Castorina
authors: Ferdinando M
authors: FM
authors: Milazzo
authors: Maria L
authors: ML
authors: Cervoni
authors: Mario B
authors: MB
authors: Guglielmi
authors: Marcella
authors: M
authors: Barbarino
authors: Rosanna
authors: R
authors: Foderà
authors: Claudio
authors: C
authors: Pisano
authors: Walter
authors: W
authors: Cabri
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D011487:Protein Conformation; D012118:Resorcinols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: C570541:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(5-(morpholinomethyl)isoxazole-3-carbonylamino)isoxazole-3-carboxylic acid ethylamide; D000577:Amides; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D012118:Resorcinols