Dispiroindolinone-Glutarimide Conjugates: Synthesis and Evaluation as Potential Hetero-PROTACs for p53 Reactivation.

Authors

Vladislav S Polyakov, Yuri K Grishin, Viktor A Tafeenko, Ekaterina S Ivanova, Sofya S Pogodaeva, Daniil V Moldavskii, Alexander A Shtil, Elena K Beloglazkina

Published in

Molecules (Basel, Switzerland). Volume 31. Issue 10. May 10, 2026. Epub May 10, 2026.

Abstract

A convergent scheme for the preparation of conjugates with the dispiroindolinone-pyrrolidine-thioimidazolone and glutarimide moieties connected via a triazole-containing linker is proposed. Target conjugates were synthesized by azide-alkyne (3+2) cycloaddition reactions between propargylthio-substituted dispiroindolinone-pyrrolidine-imidazolones and an azido-glutarimide derivative. The starting compounds were available isothiocyanates, glycine, substituted benzaldehydes, chloroacetamide, and ethyl acrylate. The key azide-alkyne (3+2) cycloaddition step was carried out using TBTA as a catalyst, achieving >70% product yields. The resulting bifunctional compounds contained a fragment of dispiroindolinone (a p53-MDM2 interaction inhibitor) and glutarimide, a ubiquitin ligase ligand. The obtained dispiroindolinone-glutarimide conjugates were tested for their potential as hetero-PROTAC compounds for p53 reactivation. Individual conjugates showed preferential cytotoxicity against HCT116 colon carcinoma cells (wild-type53) compared to the isogenic HCT116p53^-/- subline.

PMID:
42197156
Bibliographic data and abstract were imported from PubMed on 13 Sep 2026.

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