Inhibition of the MDM2-p53 protein-protein interaction is an important approach to cancer therapy. MDM2-p53 inhibitors, e.g isoindolinones 1 , reactivate p53 in MDM2 amplified cell-lines, inducing growth inhibition or apoptosis (Bio. Med. Chem. Letts, 2011, 54, 5916).  Previous isoindolinone syntheses were hampered by difficult separation of A-ring regioisomers. A versatile, regioselective synthesis of 4-substituted isoindolinones e.g. 1  was achieved using a lead-mediated rearrangement of N-acylhydrazone 2 . A small-series of 4-substitutions was investigated, demonstrating the optimal properties of chlorine at this position.

Regiospecific synthesis of isoindolinones as MDM2 inhibitors

245th National Meeting (2013)

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