Discovery of N-substituted 3-arylisoquinolone derivatives as antitumor agents originating from O-substituted 3-arylisoquinolines via [2,3] or [3,3] rearrangement

• Several N-substituted isoquinolones were obtained via [2,3] or [3,3] rearrangement.
• 4h and 4j showed strong antitumor activities close to vemurafenib and sorafenib.
• The unusual [2,3] rearrangement is a novel rearrangement observed on lactams.

The present study discovers multiple N-substituted 3-arylisoquinolone derivatives as antitumor agents originating from O-substituted 3-arylisoquinolines via [2,3] or [3,3] rearrangement. The current [2,3] rearrangement of epoxy or acetal O-substituents converting to diol or alcohol N-substituents can be promoted by silica gel or by diluted hydrochloric acid, which is distinct from previously reported [2,3] rearrangements. Some of the derivatives displayed comparable or even stronger cytotoxicity than sorafenib and vemurafenib on HCT116 colon carcinoma and A375 melanoma cell lines. Therefore, the rearrangement via intramolecular carbon-oxygen bond cleavage and carbon-nitrogen bond formation should be a useful approach for developing novel anticancer drugs derived from isoquinolones.

Several N-substituted isoquinolones were obtained via [2,3] or [3,3] rearrangement, among which, 4h and 4j showed strong antitumor activities close to vemurafenib and sorafenib.Figure optionsDownload as PowerPoint slide