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Nutlin\u20103a\u2010aa is more active than Nutlin\u20103a against purified wild\u2010type MDM2, and is more effective at increasing p53 levels and releasing transcription of p53 target genes from MDM2\u2010induced repression. X\u2010ray analysis of wild\u2010type MDM2\u2010bound Nutlin\u20103a\u2010aa indicated that the orientation of its modified piperazinone ring was altered in comparison to the piperazinone ring of MDM2\u2010bound Nutlin\u20103a, with the exocyclic methylene group of Nutlin\u20103a\u2010aa 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.<\/jats:p>","DOI":"10.1002\/cbic.202300006","type":"journal-article","created":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T15:05:54Z","timestamp":1672931154000},"update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Nutlin\u20103a\u2010aa: Improving the Bioactivity of a p53\/MDM2 Interaction Inhibitor by Introducing a Solvent\u2010Exposed Methylene Group"],"prefix":"10.1002","volume":"24","author":[{"given":"Florian","family":"Nietzold","sequence":"first","affiliation":[{"name":"Institute of Organic Chemistry Leipzig University Johannisallee 29 04103 Leipzig Germany"}]},{"given":"Stefan","family":"Rubner","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry Leipzig University Johannisallee 29 04103 Leipzig 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