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.

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.