Dispiroindolinone-Glutarimide Conjugates as Potential Hetero-PROTAC Compounds for p53 Reactivation

Aiming at p53-reactivating compounds, a convergent scheme for the preparation of conjugates with the dispiro-indolinone-pyrrolidine-thioimidazolone and glutarimide moieties connected via a triazole-containing linker were proposed. Target conjugates were synthesized by azide-alkyne cycloaddition reactions between propargylthio-substituted dispiro-indolinone-pyrrolidine-imidazolones and an azido-glutarimide derivative. The starting compounds were available isothiocyanates, glycine, substituted benzaldehydes, chloroacetamide, and ethyl acrylate. The key azide-alkyne cycloaddition step was carried out using TBTA as a catalyst, achieving >70% product yields. The resulting bifunctional compounds contained a fragment of dispiroindolinone (p53-MDM2 interaction inhibitor) and glutarimide, an ubiquitin ligase ligand. The dispiroindolinone-glutarimide conjugate with 5-bromoisatine and 4-bromophenyl moieties showed a potential for p53 re-activation as determined by preferential cytotoxicity against HCT116 colon carcinoma cells (wild type53) compared to the isogenic HCT116p53^-/- subline.