{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,9]],"date-time":"2025-11-09T03:51:20Z","timestamp":1762660280570,"version":"build-2065373602"},"reference-count":50,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T00:00:00Z","timestamp":1674086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UIDB\/04138\/2020","UIDB\/00100\/2020","UIDP\/00100\/2020","LA\/P\/0056\/2020","UID\/QUI\/50006\/2020","PTDC\/QUI-QOR\/29664\/2017","PTDC\/QUI-QOR\/1304\/2020","PD\/BD\/143126\/2019","COVID\/BD\/152557\/2022","RNEM-LISBOA-01-0145-FEDER-402-022125"],"award-info":[{"award-number":["UIDB\/04138\/2020","UIDB\/00100\/2020","UIDP\/00100\/2020","LA\/P\/0056\/2020","UID\/QUI\/50006\/2020","PTDC\/QUI-QOR\/29664\/2017","PTDC\/QUI-QOR\/1304\/2020","PD\/BD\/143126\/2019","COVID\/BD\/152557\/2022","RNEM-LISBOA-01-0145-FEDER-402-022125"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>For the first time, the pharmacokinetic (PK) profile of tryptophanol-derived isoindolinones, previously reported as p53 activators, was investigated. From the metabolites\u2019 identification, performed by liquid chromatography coupled to high resolution tandem mass spectrometry (LC-HRMS\/MS), followed by their preparation and structural elucidation, it was possible to identify that the indole C2 and C3 are the main target of the cytochrome P450 (CYP)-promoted oxidative metabolism in the tryptophanol-derived isoindolinone scaffold. Based on these findings, to search for novel p53 activators a series of 16 enantiopure tryptophanol-derived isoindolinones substituted with a bromine in indole C2 was prepared, in yields of 62\u201389%, and their antiproliferative activity evaluated in human colon adenocarcinoma HCT116 cell lines with and without p53. Structural optimization led to the identification of two (S)-tryptophanol-derived isoindolinones 3.9-fold and 1.9-fold more active than hit SLMP53-1, respectively. Compounds\u2019 metabolic stability evaluation revealed that this substitution led to a metabolic switch, with the impact of Phase I oxidative metabolism being minimized. Through differential scanning fluorimetry (DSF) experiments, the most active compound of the series in cell assays led to an increase in the protein melting temperature (Tm) of 10.39 \u00b0C, suggesting an effective binding to wild-type p53 core domain.<\/jats:p>","DOI":"10.3390\/ph16020146","type":"journal-article","created":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T05:06:14Z","timestamp":1674104774000},"page":"146","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Metabolism-Guided Optimization of Tryptophanol-Derived Isoindolinone p53 Activators"],"prefix":"10.3390","volume":"16","author":[{"given":"Valentina","family":"Barcherini","sequence":"first","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"given":"Joana B.","family":"Loureiro","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Laborat\u00f3rio de Microbiologia, Departamento de Ci\u00eancias Biol\u00f3gicas, Faculdade de Farm\u00e1cia, Universidade do Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5397-8684","authenticated-orcid":false,"given":"Ana","family":"Sena","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural (CQE), Institute of Molecular Sciences, Departamento de Engenharia Qu\u00edmica, Instituto Superior T\u00e9cnico (IST), Universidade de Lisboa, 1049-001 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3973-6843","authenticated-orcid":false,"given":"Catarina","family":"Madeira","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2946-9342","authenticated-orcid":false,"given":"Paula","family":"Leandro","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9531-4939","authenticated-orcid":false,"given":"Luc\u00edlia","family":"Saraiva","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Laborat\u00f3rio de Microbiologia, Departamento de Ci\u00eancias Biol\u00f3gicas, Faculdade de Farm\u00e1cia, Universidade do Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1827-7369","authenticated-orcid":false,"given":"Alexandra M. M.","family":"Antunes","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural (CQE), Institute of Molecular Sciences, Departamento de Engenharia Qu\u00edmica, Instituto Superior T\u00e9cnico (IST), Universidade de Lisboa, 1049-001 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2239-9353","authenticated-orcid":false,"given":"Maria M. M.","family":"Santos","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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