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. (30th April 2015)

• Record Type: Journal Article
• Authors: Musso, Loana; Cincinelli, Raffaella; Giannini, Giuseppe; Manetti, Fabrizio; Dallavalle, Sabrina
• Is Part Of: Chemical biology & drug design. Volume 86:Number 5(2015:Nov.)
• Page Start: 1030
• Page End: 1035
• Publication Date: 2015-04-30
• Subjects: anticancer -- docking calculations -- Hsp90 inhibitors -- isoxazoles -- synthesis; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12570
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract : A novel class of 5, 6‐dihydro‐4 H ‐benzo[ d ]isoxazol‐7‐ones and 5, 6‐dihydro‐4 H ‐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‐1 H ‐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. Abstract : A series of 5, 6‐dihydro‐4 H ‐benzo[ d ]isoxazol‐7‐ones and 5, 6‐dihydro‐4 H ‐isoxazolo[5, 4‐ c ]pyridin‐7‐ones was designed, synthesized, and assayed to investigate affinity toward Hsp90 protein. Compounds 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.