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Nutlin-3a-aa: Improving the Bioactivity of a p53/MDM2 Interaction Inhibitor by Introducing a Solvent-Exposed Methylene Group |
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| Authors: | Dr. Florian Nietzold Dr. Stefan Rubner Dr. Beata Labuzek Dr. Przemysław Golik Dr. Ewa Surmiak Xabier del Corte Dr. Radoslaw Kitel Christoph Protzel Regina Reppich-Sacher Dr. Jan Stichel Dr. Katarzyna Magiera-Mularz Prof. Dr. Tad A. Holak Prof. Dr. Thorsten Berg |
| Affiliation: | 1. Institute of Organic Chemistry, Leipzig University, Johannisallee 29, 04103 Leipzig, Germany;2. Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland;3. Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland Present address: Departamento de Química Orgánica I, Centro de Investigación y Estudios Avanzados “Lucio Lascaray”, Facultad de Farmacia, University of the Basque Country, UPV/EHU Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain;4. Institute of Biochemistry, Leipzig University, Brüderstraße 34, 04103 Leipzig, Germany |
| Abstract: | 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. |
| Keywords: | biological activity drug design inhibitors protein structures protein-protein interactions |