Synthesis, Structural Characterisation, and Preliminary Evaluation of Non-Indolin-2-one-based Angiogenesis Inhibitors Related to Sunitinib (Sutent®)

The indolin-2-one fused-ring system and the 2,4-dimethylpyrrole unit represent key structural motifs in the anticancer drug sunitinib (Sutent (R)) and predecessor angiogenesis inhibitors that have undergone anticancer clinical trials (e.g. semaxanib, SU5416). In pursuit of novel anti-angiogenic scaffolds, we were interested in identifying whether the indolin-2-one group in these structures could be modified without losing activity. This paper describes novel condensation chemistry used to prepare a test series of (E)- and (Z)-alkenes related to SU5416 that retain the 2,4-dimethylpyrrole unit while incorporating ring-opened indolin-2-ones. Unique structural characteristics were identified in the compounds, such as intramolecular hydrogen bonds in the (Z)-alkenes, and several examples were shown to possess significant anti-angiogenic activity in a rat aorta in vitro model of angiogenesis. The work demonstrates that the indolin-2-one moiety is not an absolute requirement for angiogenesis inhibition in the sunitinib/SU5416 class.