Overman rearrangement and Pomeranz-Fritsch reaction for the synthesis of benzoazepinoisoquinolones to discover novel antitumor agents

The B-ring of Benzoazepinoisoquinolones 1a-b was successfully constructed by Pomeranz-Fritsch reaction. The key intermediates 5a-b could be transformed from 9a-b via Overman rearrangement. The bioassay showed that 11 compounds are more active than sorafenib (IC₅₀ = 7.56 μM) against A375 melanoma cell line, among which 1a, 5a, 8a and 10c with IC₅₀ values of 0.59, 0.20, 0.17 and 0.11 μM, respectively, showed potent cytotoxicity close to or even stronger than the anti-melanoma drug vemurafenib (IC₅₀ = 0.18 μM). In addition, 5a, 8a and 10c are more active than both vemurafenib and sorafenib on HCT116 colon cell line (IC₅₀ values: 0.86, 0.65, 0.42, >30 and 5.65 μM for 5a, 8a, 10c, vemurafenib and sorafenib). Therefore, these compounds are promising candidates for further drug development.

Antitumor; Benzoazepinoisoquinolone; N-Allylated 3-arylisoquinolone; Overman rearrangement; Pomeranz–Fritsch reaction.