Nutlin‐3a‐aa: Improving the Bioactivity of a p53/MDM2 Interaction Inhibitor by Introducing a Solvent‐Exposed Methylene Group

Nutlin‐3a is a reversible inhibitor of the p53/MDM2 interaction. We have synthesized the derivative Nutlin‐3a‐aa bearing an additional exocyclic methylene group in the piperazinone moiety. Nutlin‐3a‐aa is more active than Nutlin‐3a against purified wild‐type MDM2, and is more effective at increasing p53 levels and releasing transcription of p53 target genes from MDM2‐induced repression. X‐ray analysis of wild‐type MDM2‐bound Nutlin‐3a‐aa indicated that the orientation of its modified piperazinone ring was altered in comparison to the piperazinone ring of MDM2‐bound Nutlin‐3a, with the exocyclic methylene group of Nutlin‐3a‐aa pointing away from the protein surface. Our data point to the introduction of exocyclic methylene groups as a useful approach by which to tailor the conformation of bioactive molecules for improved biological activity. Look away. Modification of the p53/MDM2 inhibitor Nutlin‐3a with an exocyclic methylene group generated the more potent inhibitor Nutlin‐3a‐aa. X‐ray analysis of MDM2‐bound Nutlin‐3a‐aa indicated that the exocyclic methylene group of Nutlin‐3a‐aa faces away from the protein surface. Our data suggest the introduction of exocyclic methylene groups as a possible approach by which to optimize the conformation of bioactive molecules.