Potency and Selectivity Optimization of Tryptophanol‐Derived Oxazoloisoindolinones: Novel p53 Activators in Human Colorectal Cancer
dc.contributor.author | Barcherini, Valentina | |
dc.contributor.author | Almeida, Joana | |
dc.contributor.author | Lopes, Elizabeth A. | |
dc.contributor.author | Wang, Mi | |
dc.contributor.author | Magalhães E Silva, Diogo | |
dc.contributor.author | Mori, Mattia | |
dc.contributor.author | Wang, Shaomeng | |
dc.contributor.author | Saraiva, Lucília | |
dc.contributor.author | Santos, Maria M. M. | |
dc.date.accessioned | 2021-02-04T21:52:45Z | |
dc.date.available | 2022-02-04 16:52:43 | en |
dc.date.available | 2021-02-04T21:52:45Z | |
dc.date.issued | 2021-01-08 | |
dc.identifier.citation | Barcherini, Valentina; Almeida, Joana; Lopes, Elizabeth A.; Wang, Mi; Magalhães E Silva, Diogo ; Mori, Mattia; Wang, Shaomeng; Saraiva, Lucília ; Santos, Maria M. M. (2021). "Potency and Selectivity Optimization of Tryptophanol‐Derived Oxazoloisoindolinones: Novel p53 Activators in Human Colorectal Cancer." ChemMedChem 16(1): 250-258. | |
dc.identifier.issn | 1860-7179 | |
dc.identifier.issn | 1860-7187 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/166244 | |
dc.description.abstract | To search for novel p53 activators, four series of novel (S)‐ and (R)‐tryptophanol‐derived oxazoloisoindolinones were synthesized in a straightforward manner and their antiproliferative activity was evaluated in the human colorectal cancer HCT116 cell line. Structural optimization of the hit compound SLMP53‐1 led to the identification of a (R)‐tryptophanol‐derived isoindolinone that was found to be six‐fold more active, with increased selectivity for HCT116 cells with p53 and with low toxicity in normal cells. Binding studies with MDM2 showed that the antiproliferative activity of tryptophanol‐derived isoindolinones does not involve inhibition of the main negative regulator of the p53 protein. Molecular docking simulations showed that although these molecules establish hydrophobic interactions with MDM2, they do not possess the required features to bind MDM2.Hunting p53 activators: Hit‐to‐lead optimization of the (S)‐tryptophanol‐derived oxazoloisoindolinone SLMP53‐1 led to the development of a chemical library of 34 enantiomerically pure analogues. The compounds were screened in cancer and normal colon cells. From this screening, emerged a novel (R)‐tryptophanol derivative with increased in vitro potency and selectivity in p53 expressing HCT116 cells compared with SLMP53‐1. | |
dc.publisher | Wiley Periodicals, Inc. | |
dc.subject.other | Tryptophanol | |
dc.subject.other | p53 | |
dc.subject.other | MDM2 | |
dc.subject.other | Isoindolinones | |
dc.subject.other | Cancer | |
dc.title | Potency and Selectivity Optimization of Tryptophanol‐Derived Oxazoloisoindolinones: Novel p53 Activators in Human Colorectal Cancer | |
dc.type | Article | |
dc.rights.robots | IndexNoFollow | |
dc.subject.hlbsecondlevel | Natural Resources and Environmen | |
dc.subject.hlbtoplevel | Science | |
dc.description.peerreviewed | Peer Reviewed | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/166244/1/cmdc202000522.pdf | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/166244/2/cmdc202000522-sup-0001-misc_information.pdf | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/166244/3/cmdc202000522_am.pdf | |
dc.identifier.doi | 10.1002/cmdc.202000522 | |
dc.identifier.doi | https://dx.doi.org/10.7302/167 | |
dc.identifier.source | ChemMedChem | |
dc.identifier.citedreference | S. S. Batsanov, Inorg. Mater. Transl. from Neorg. Mater. Orig. Russ. Text 2001, 37, 1031 - 1 –46. | |
dc.identifier.citedreference | M. J. Duffy, N. C. Synnott, J. Crown, Eur. J. Cancer 2017, 83, 258 – 265. | |
dc.identifier.citedreference | V. J. N. Bykov, S. E. Eriksson, J. Bianchi, K. G. Wiman, Nat. Rev. Cancer 2018, 18, 89 – 102. | |
dc.identifier.citedreference | E. A. Lopes, S. Gomes, L. Saraiva, M. M. M. Santos, Curr. Med. Chem. 2018, 26, 7323 – 7336. | |
dc.identifier.citedreference | S. Jeay, S. Ferretti, P. Holzer, J. Fuchs, E. A. Chapeau, M. Wartmann, D. Sterker, V. Romanet, M. Murakami, G. Kerr, et al., Cancer Res. 2018, 78, 6257 – 6267. | |
dc.identifier.citedreference | M. J. G. W. Ladds, S. Laín, J. Mol. Cell Biol. 2019, 11, 245 – 254. | |
dc.identifier.citedreference | C. J. A. Ribeiro, J. D. Amaral, C. M. P. Rodrigues, R. Moreira, M. M. M. Santos, Bioorg. Med. Chem. 2014, 22, 577 – 584. | |
dc.identifier.citedreference | Â. Monteiro, L. M. Gonçalves, M. M. M. Santos, Eur. J. Med. Chem. 2014, 79, 266 – 272. | |
dc.identifier.citedreference | J. Soares, N. A. L. Pereira, Â. Monteiro, M. Leão, C. Bessa, D. J. V. A. Dos Santos, L. Raimundo, G. Queiroz, A. Bisio, A. Inga, et al., Eur. J. Pharm. Sci. 2015, 66, 138 – 147. | |
dc.identifier.citedreference | C. J. A. Ribeiro, J. D. Amaral, C. M. P. Rodrigues, R. Moreira, M. M. M. Santos, MedChemComm 2016, 7, 420 – 425. | |
dc.identifier.citedreference | J. Soares, L. Raimundo, N. A. L. Pereira, Â. Monteiro, S. Gomes, C. Bessa, C. Pereira, G. Queiroz, A. Bisio, J. Fernandes, et al., Oncotarget 2015, 7, 4326 – 4343. | |
dc.identifier.citedreference | J. Soares, M. Espadinha, L. Raimundo, H. Ramos, A. S. Gomes, S. Gomes, J. B. Loureiro, A. Inga, F. Reis, C. Gomes, et al., Mol. Oncol. 2017, 11, 612 – 627. | |
dc.identifier.citedreference | S. Gomes, B. Bosco, J. B. Loureiro, H. Ramos, L. Raimundo, J. Soares, N. Nazareth, V. Barcherini, C. Oliveira, A. Bisio, et al., Cancers 2019, 11, 1151 – 1171. | |
dc.identifier.citedreference | N. A. L. Pereira, Â. Monteiro, M. Machado, J. Gut, E. Molins, M. J. Perry, J. Dourado, R. Moreira, P. J. Rosenthal, M. Prudêncio, et al., ChemMedChem 2015, 10, 2080 – 2089. | |
dc.identifier.citedreference | N. A. L. Pereira, F. X. Sureda, M. Turch, M. Amat, J. Bosch, M. M. M. Santos, Monatsh. Chem. 2013, 144, 473 – 477. | |
dc.identifier.citedreference | B. Vogelstein, D. Lane, A. J. Levine, Nature 2000, 408, 307 – 310. | |
dc.identifier.citedreference | K. Mierzejewska, M. Bochtler, H. Czapinska, Nucleic Acids Res. 2016, 44, 485 – 495. | |
dc.identifier.citedreference | I. R. Hardcastle, S. U. Ahmed, H. Atkins, A. H. Calvert, N. J. Curtin, G. Farnie, B. T. Golding, R. J. Griffin, S. Guyenne, C. Hutton, et al., Bioorg. Med. Chem. Lett. 2005, 15, 1515 – 1520. | |
dc.identifier.citedreference | I. R. Hardcastle, S. U. Ahmed, H. Atkins, G. Farnie, B. T. Golding, R. J. Griffin, S. Guyenne, C. Hutton, P. Källblad, S. J. Kemp, et al., J. Med. Chem. 2006, 49, 6209 – 6221. | |
dc.identifier.citedreference | A. F. Watson, J. Liu, K. Bennaceur, C. J. Drummond, J. A. Endicott, B. T. Golding, R. J. Griffin, K. Haggerty, X. Lu, J. M. McDonnell, et al., Bioorg. Med. Chem. Lett. 2011, 21, 5916 – 5919. | |
dc.identifier.citedreference | T. A. Grigoreva, D. S. Novikova, A. V. Petukhov, M. A. Gureev, A. V. Garabadzhiu, G. Melino, N. A. Barlev, V. G. Tribulovich, Bioorg. Med. Chem. Lett. 2017, 27, 5197 – 5202. | |
dc.identifier.citedreference | I. R. Hardcastle, J. Liu, E. Valeur, A. Watson, U. Ahmed, T. J. Blackburn, K. Bennaceur, W. Clegg, C. Drummond, J. A. Endicott, et al., J. Med. Chem. 2011, 2, 1233 – 1243. | |
dc.identifier.citedreference | A. S. Gomes, H. Ramos, S. Gomes, J. B. Loureiro, J. Soares, V. Barcherini, P. Monti, G. Fronza, C. Oliveira, L. Domingues, et al., Biochim. Biophys. Acta Gen. Subj. 2020, 1864, 129440. | |
dc.identifier.citedreference | N. A. L. Pereira, F. X. Sureda, M. Pérez, M. Amat, M. M. M. Santos, Molecules 2016, 21, 1 – 12. | |
dc.identifier.citedreference | Y. Zhao, S. Yu, W. Sun, L. Liu, J. Lu, D. McEachern, S. Shargary, D. Bernard, X. Li, T. Zhao, et al., J. Med. Chem. 2013, 56, 5553 – 5561. | |
dc.identifier.citedreference | Y. Rew, D. Sun, X. Yan, H. P. Beck, J. Canon, A. Chen, J. Duquette, J. Eksterowicz, B. M. Fox, J. Fu, et al., J. Med. Chem. 2014, 57, 10499 – 10511. | |
dc.identifier.citedreference | P. C. D. Hawkins, A. G. Skillman, G. L. Warren, B. A. Ellingson, M. T. Stahl, J. Chem. Inf. Model. 2010, 50, 572 – 584. | |
dc.identifier.citedreference | M. McGann, J. Chem. Inf. Model. 2011, 51, 578 – 596. | |
dc.identifier.citedreference | M. McGann, J. Comput.-Aided Mol. Des. 2012, 26, 897 – 906. | |
dc.identifier.citedreference | F. Bray, J. Ferlay, I. Soerjomataram, R. L. Siegel, L. A. Torre, A. Jemal, CA. Cancer J. Clin. 2018, 68, 394 – 424. | |
dc.identifier.citedreference | R. L. Siegel, K. D. Miller, A. Jemal, CA. Cancer J. Clin. 2019, 69, 7 – 34. | |
dc.identifier.citedreference | L. Cheng, C. Eng, L. Z. Nieman, A. S. Kapadia, X. L. Du, Am. J. Clin. Oncol. Cancer Clin. Trials 2011, 34, 573 – 580. | |
dc.identifier.citedreference | K. Thanikachalam, G. Khan, Nutrients 2019, 11, 164 – 175. | |
dc.identifier.citedreference | C. Sawyers, Nature 2004, 432, 294 – 297. | |
dc.identifier.citedreference | K. H. Khoo, K. K. Hoe, C. S. Verma, D. P. Lane, Nat. Rev. Drug Discov. 2014, 13, 217 – 36. | |
dc.identifier.citedreference | A. C. Joerger, A. R. Fersht, Annu. Rev. Biochem. 2016, 85, 375 – 404. | |
dc.identifier.citedreference | E. R. Kastenhuber, S. W. Lowe, Cell 2017, 170, 1062 – 1078. | |
dc.identifier.citedreference | X. L. Li, J. Zhou, Z. R. Chen, W. J. Chng, World J. Gastroenterol. 2015, 21, 84 – 93. | |
dc.identifier.citedreference | M. L. Slattery, L. E. Mullany, R. K. Wolff, L. C. Sakoda, W. S. Samowitz, J. S. Herrick, Genomics 2019, 111, 762 – 771. | |
dc.identifier.citedreference | K. T. Bieging, Nat. Rev. Cancer 2014, 14, 359 – 370. | |
dc.identifier.citedreference | J. Chen, Cold Spring Harb. Perspect. Biol. 2016, 1 – 16. | |
dc.identifier.citedreference | K. H. Vousden, K. M. Ryan, Nat. Rev. Cancer 2009, 9, 691 – 700. | |
dc.identifier.citedreference | L. Galluzzi, G. Pierron, P. Codogno, F. Cecconi, E. Morselli, U. Nannmark, F. Madeo, G. Kroemer, G. Szabadkai, N. Tavernarakis, et al., Nat. Cell Biol. 2008, 10, 676 – 687. | |
dc.identifier.citedreference | T. Li, N. Kon, L. Jiang, M. Tan, T. Ludwig, Y. Zhao, R. Baer, W. Gu, Cell 2012, 149, 1269 – 1283. | |
dc.identifier.citedreference | M. Wade, Y. C. Li, G. M. Wahl, Nat. Rev. Cancer 2013, 13, 83 – 96. | |
dc.identifier.citedreference | P. A. J. Muller, K. H. Vousden, Cancer Cell 2014, 25, 304 – 317. | |
dc.identifier.citedreference | M. Espadinha, V. Barcherini, E. A. Lopes, M. M. M. Santos, Curr. Top. Med. Chem. 2018, 18, 647 – 660. | |
dc.identifier.citedreference | X. Liu, R. Wilcken, A. C. Joerger, I. S. Chuckowree, J. Amin, J. Spencer, A. R. Fersht, Nucleic Acids Res. 2013, 41, 6034 – 6044. | |
dc.working.doi | 10.7302/167 | en |
dc.owningcollname | Interdisciplinary and Peer-Reviewed |
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