A Diarylpentanoid with Potential Activation of the p53 Pathway: Combination of in silico Screening Studies, Synthesis, and Biological Activity Evaluation

• Type: Article in International Scientific Journal
• Date: 2021

Authors

Moreira, J (Author) Other; Almeida, J (Author) Other; Loureiro, JB (Author) Other; Ramos, H (Author) Other; Palmeira, A (Author) FFUP; Pinto, MM (Author) Other; Lucilia Saraiva (Author) FFUP; Honorina Cidade (Author) FFUP

Journal

Title: ChemMedChem

Vol. 16

Pages: 2969-2981

ISSN: 1860-7179

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 2 Citations

Other information

Authenticus ID: P-00V-78V

DOI: 10.1002/cmdc.202100337

Abstract (EN): In silico studies of a library of diarylpentanoids led us to the identification of potential new MDM2/X ligands. The diarylpentanoids with the best docking scores obeying the druglikeness and ADMET prediction properties were subsequently synthesized and evaluated for their antiproliferative activity on colon cancer HCT116 and fibroblasts HFF-1 cells. The effect on p53-MDM2/X interactions was evaluated through yeast-based assays for compounds showing potent antiproliferative activity in HCT116 cells and low toxicity in normal cells, resulting in the identification of a potential dual inhibitor. Moreover, its antiproliferative effect was significantly reduced in the absence of p53 and in MDA-MB-231 cells expressing a mutant p53 form. The antiproliferative effect of this compound was associated with induction of cell cycle arrest, apoptosis, PARP cleavage and increased p53 and its transcriptional targets, p21 and PUMA, in HCT116 cells. Docking poses and residues involved in the inhibition of p53-MDM2/X interactions were predicted by docking studies.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 14