Potency and Selectivity Optimization of Tryptophanol-Derived Oxazoloisoindolinones: Novel p53 Activators in Human Colorectal Cancer

• Tipo: Artigo em Revista Científica Internacional
• Data: 2020

Autores

Barcherini, V (Autor) Outra; Almeida, J (Autor) Outra; Lopes, EA (Autor) Outra; Wang, M (Autor) Outra; Magalhaes e Silva, DME (Autor) Outra; Mori, M (Autor) Outra; Wang, SM (Autor) Outra; Lucilia Saraiva (Autor) FFUP; Santos, MMM (Autor) Outra

Revista

Título: ChemMedChem

ISSN: 1860-7179

Editora: Wiley-Blackwell

Indexação

ISI Web of Knowledge - 3 Citações

Scopus - 3 Citações

Outras Informações

ID Authenticus: P-00S-NV3

DOI: 10.1002/cmdc.202000522

Abstract (EN): 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.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 10