title: Synthesis of 5,6-dihydro-4H-benzo[d]isoxazol-7-one and 5,6-dihydro-4H-isoxazolo[5,4-c]pyridin-7-one derivatives as potential Hsp90 inhibitors.
abstract: A novel class of 5,6-dihydro-4H-benzo[d]isoxazol-7-ones and 5,6-dihydro-4H-isoxazolo[5,4-c]pyridin-7-ones was designed, synthesized, and assayed to investigate the affinity toward Hsp90 protein. The synthetic route was based on a 1,3-dipolar cycloaddition of nitriloxides, generated in situ from suitable benzaldoximes, with 2-bromocyclohex-2-enones or 3-bromo-5,6-dihydro-1H-pyridin-2-ones. Whereas all the compounds bearing a benzamide group on the bicyclic scaffold were devoid of activity, the derivatives carrying a resorcinol-like fragment showed a remarkable inhibitory effect on Hsp90. Docking calculations were performed to investigate the orientation of the new compounds within the binding site of the enzyme.
authors: Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, University of Milano, via Celoria 2, Milan, I-20133, Italy.
authors: Loana
authors: L
authors: Musso
authors: Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, University of Milano, via Celoria 2, Milan, I-20133, Italy.
authors: Raffaella
authors: R
authors: Cincinelli
authors: R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., via Pontina Km 30,400, Pomezia, I-00040, Italy.
authors: Giuseppe
authors: G
authors: Giannini
authors: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via A. Moro 2, Siena, I-53100, Italy.
authors: Fabrizio
authors: F
authors: Manetti
authors: Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, University of Milano, via Celoria 2, Milan, I-20133, Italy.
authors: Sabrina
authors: S
authors: Dallavalle
mesh_terms: D001665:Binding Sites; D061565:Cycloaddition Reaction; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D011725:Pyridines
keywords: Hsp90 inhibitors; anticancer; docking calculations; isoxazoles; synthesis