Please login first
Tryptophanol-derived oxazoloisoindolinones: Novel small molecule p53 activators with promising antitumor activity
1 , 2 , 1 , 2 , 2 , 3 , 3 , 4 , 2 , * 1
1  iMed.ULisboa, Faculdade de Farmácia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
2  LAQV/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
3  Institute of Pharmacology & Experimental Therapeutics, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, CNC.IBILI Consortium & CIBB Consortium, University of Coimbra, Coimbra, Portugal
4  Centro de Química Estrutural, Instituto Superior Técnico, University of Lisbon, Av. Rovisco Pais, 1049 001, Lisboa, Portugal


The tumour suppressor p53 is a pivotal target in cancer therapy as this protein is inactive in all human cancers. In the last years, our research group has been working on the design and synthesis of novel small molecules that are able to reactivate p53.[1] Of these, novel scaffolds containing the oxazoloisoindolinone moiety in their chemical structure emerged with very promising anti-cancer properties.[2] In this communication an overview about the therapeutic potential of a tryptophanol-derived oxazoloisoindolinone chemical library as selective p53 activators will be given. Based on the hit tryptophanol-derived small molecule SLMP53-1, identified as a wild-type and mutant p53 reactivator, a second series of compounds was prepared leading to DIMP53-1 (a p53-MDM2/X interactions dual inhibitor) and to SLMP53-2 (small molecule able to restore the wild-type function of mut p53Y220C). The tryptophanol-derived oxazoloisoindolinone chemical family was prepared by a stereoselective cyclocondensation reaction of enantiopure aminoalcohol tryptophanol with several commercially available oxoacids. From the screening of this library, several very promising molecules emerged with potent anticancer activity against aggressive cancers. The anticancer activity and mechanism of action of the target molecules was studied in human colon adenocarcinoma HCT116 cells with wild-type p53 (HCT116 p53+/+) and the corresponding p53-null isogenic derivative cells (HCT116 p53-/-), as well as in several cancer cell lines with different p53 status. The most promising molecules were also evaluated in vivo.

REFERENCES: 1. a) J. D. Amaral et al. Chem. 2019, 7, 15; b) L. Raimundo et al. British J. Pharmacol. 2018, 175, 3947; c) R. C. Nunes et al. Eur. J. Med. Chem. 2017, 139, 168. 2. a) S. Gomes et al., Cancers 2019, 11, 1151; b) J. Soares et al. Mol. Oncol. 2017; 11; 612; c) J. Soares et al. Oncotarget 2016, 7, 4326; d) J. Soares et al. Eur. J. Pharm. Sci. 2015, 66, 138.

ACKNOWLEDGMENTS: We thank PT national funds (FCT/MCTES, Fundação para a Ciência e Tecnologia and Ministério da Ciência, Tecnologia e Ensino Superior) the funding through grants PTDC/QUI-QOR/29664/2017, UID/DTP/04138/2019 (iMed.ULisboa), UID/QUI/00100/2019 (CQE) and UID/QUI/50006/2019, the principal investigator grants CEECIND/02001/2017 (A. M. M. Antunes) and CEECIND/01772/2017 (M. M. M. Santos), and the PhD fellowships PD/BD/143126/2019 (V. Barcherini), SFRH/BD/96189/2013 (S. Gomes) and SFRH/BD/117931/2016 (M. Espadinha).

Keywords: Cancer; MDMs; p53; tryptophanol; isoindolinone