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

• Type: Article in International Scientific Journal
• Date: 2020

Authors

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

Journal

Title: ChemMedChem

ISSN: 1860-7179

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 3 Citations

Scopus - 3 Citations

Other information

Authenticus ID: 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 10