{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2023,8,23]],"date-time":"2023-08-23T04:59:49Z","timestamp":1692766789525},"reference-count":48,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T00:00:00Z","timestamp":1676505600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemBioChem"],"published-print":{"date-parts":[[2023,3,14]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Nutlin\u20103a is a reversible inhibitor of the p53\/MDM2 interaction. We have synthesized the derivative Nutlin\u20103a\u2010aa bearing an additional exocyclic methylene group in the piperazinone moiety. 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 Germany"}]},{"given":"Beata","family":"Labuzek","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry Faculty of Chemistry Jagiellonian University  Gronostajowa 2 30-387 Krakow Poland"}]},{"given":"Przemys\u0142aw","family":"Golik","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry Faculty of Chemistry Jagiellonian University  Gronostajowa 2 30-387 Krakow Poland"}]},{"given":"Ewa","family":"Surmiak","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry Faculty of Chemistry Jagiellonian University  Gronostajowa 2 30-387 Krakow Poland"}]},{"given":"Xabier","family":"del Corte","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry Faculty of Chemistry Jagiellonian University  Gronostajowa 2 30-387 Krakow Poland"},{"name":"Present address: Departamento de Qu\u00edmica Org\u00e1nica I Centro de Investigaci\u00f3n y Estudios Avanzados \u201cLucio Lascaray\u201d Facultad de Farmacia University of the Basque Country  UPV\/EHU Paseo de la Universidad 7 01006 Vitoria-Gasteiz Spain"}]},{"given":"Radoslaw","family":"Kitel","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry Faculty of Chemistry Jagiellonian University  Gronostajowa 2 30-387 Krakow Poland"}]},{"ORCID":"http:\/\/orcid.org\/0000-0002-7910-6371","authenticated-orcid":false,"given":"Christoph","family":"Protzel","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry Leipzig University  Johannisallee 29 04103 Leipzig Germany"}]},{"given":"Regina","family":"Reppich\u2010Sacher","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry Leipzig University  Br\u00fcderstra\u00dfe 34 04103 Leipzig Germany"}]},{"given":"Jan","family":"Stichel","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry Leipzig University  Br\u00fcderstra\u00dfe 34 04103 Leipzig Germany"}]},{"given":"Katarzyna","family":"Magiera\u2010Mularz","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry Faculty of Chemistry Jagiellonian University  Gronostajowa 2 30-387 Krakow Poland"}]},{"given":"Tad A.","family":"Holak","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry Faculty of Chemistry Jagiellonian University  Gronostajowa 2 30-387 Krakow Poland"}]},{"ORCID":"http:\/\/orcid.org\/0000-0003-3109-7696","authenticated-orcid":false,"given":"Thorsten","family":"Berg","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry Leipzig University  Johannisallee 29 04103 Leipzig Germany"}]}],"member":"311","published-online":{"date-parts":[[2023,2,16]]},"reference":[{"key":"e_1_2_8_1_1","unstructured":"\u00a0"},{"key":"e_1_2_8_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/358015a0"},{"key":"e_1_2_8_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(98)00296-8"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20269"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s000180050273"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/26.15.3453"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201500487"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1092472"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.597"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1039\/C9CC07795B"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/ml4000657"},{"key":"e_1_2_8_12_1","unstructured":"The PyMOL Molecular Graphics System Version 0.99 Schr\u00f6dinger LLC."},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo9611834"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1080\/15257770701527794"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/0040-4039(94)88507-9"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo401321a"},{"key":"e_1_2_8_17_1","unstructured":"\u00a0"},{"key":"e_1_2_8_18_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo00227a041"},{"key":"e_1_2_8_19_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo00266a028"},{"key":"e_1_2_8_20_1","unstructured":"\u00a0"},{"key":"e_1_2_8_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr500043b"},{"key":"e_1_2_8_22_2","doi-asserted-by":"publisher","DOI":"10.1517\/17460440903232623"},{"key":"e_1_2_8_23_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.274.5292.1531"},{"key":"e_1_2_8_24_1","unstructured":"\u00a0"},{"key":"e_1_2_8_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnmrs.2007.04.001"},{"key":"e_1_2_8_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnmrs.2013.02.001"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi000930v"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2021.105422"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.6b00596"},{"key":"e_1_2_8_30_1","unstructured":"\u00a0"},{"key":"e_1_2_8_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201303207"},{"key":"e_1_2_8_31_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201303207"},{"key":"e_1_2_8_32_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr200060g"},{"key":"e_1_2_8_33_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm3003697"},{"key":"e_1_2_8_34_1","unstructured":"\u00a0"},{"key":"e_1_2_8_35_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja105875e"},{"key":"e_1_2_8_36_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo035735b"},{"key":"e_1_2_8_37_1","unstructured":"\u00a0"},{"key":"e_1_2_8_38_2","doi-asserted-by":"publisher","DOI":"10.1039\/c1cc11782c"},{"key":"e_1_2_8_39_2","doi-asserted-by":"publisher","DOI":"10.3762\/bjoc.9.267"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2004.05.055"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444913000061"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0021889807021206"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444910007493"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444911001314"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/355472a0"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"e_1_2_8_47_1","unstructured":"F. Nietzold Dissertation Leipzig University (Germany) 2019."}],"container-title":["ChemBioChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cbic.202300006","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cbic.202300006","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cbic.202300006","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T18:35:25Z","timestamp":1692729325000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cbic.202300006"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,16]]},"references-count":48,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2023,3,14]]}},"alternative-id":["10.1002\/cbic.202300006"],"URL":"http:\/\/dx.doi.org\/10.1002\/cbic.202300006","archive":["Portico"],"relation":{},"ISSN":["1439-4227","1439-7633"],"issn-type":[{"value":"1439-4227","type":"print"},{"value":"1439-7633","type":"electronic"}],"subject":["Organic Chemistry","Molecular Biology","Molecular Medicine","Biochemistry"],"published":{"date-parts":[[2023,2,16]]},"assertion":[{"value":"2023-01-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-02-16","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}