Targeting the MDM2-p53 protein-protein interaction with prenylchalcones: Synthesis of a small library and evaluation of potential antitumor activity

• Type: Article in International Scientific Journal
• Date: 2018

Authors

Brandao, P (Author) Other; Loureiro, JB (Author) Other; Carvalho, S (Author) Other; Hamadou, MH (Author) Other; Sara Cravo (Author) FFUP; Moreira, J (Author) Other; Pereira, D (Author) Other; Palmeira, A (Author) FFUP; Pinto, M (Author) Other; Lucilia Saraiva (Author) FFUP; Honorina Cidade (Author) FFUP

Journal

Title: European Journal of Medicinal Chemistry

Vol. 156

Pages: 711-721

ISSN: 0223-5234

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 20 Citations

Scopus - 20 Citations

Other information

Authenticus ID: P-00P-193

DOI: 10.1016/j.ejmech.2018.07.037

Abstract (EN): Prenylation of several bioactive scaffolds is a very interesting strategy used in Medicinal Chemistry in order to improve biological/pharmacological effects. A small library of prenylchalcones was synthesized and evaluated for the ability to inhibit the MDM2-p53 interaction using a yeast-based assay. The capacity of all synthesized prenylchalcones and their non-prenylated precursors to inhibit the growth of human colon tumor HCT116 cells was also evaluated. The obtained results led to the identification of a hit compound, prenylchalcone 2e, which behaved as potential inhibitor of the MDM2-p53 interaction in yeast, and showed improved cytotoxicity against human tumor cells expressing wild-type p53, including liver hepatocellular carcinoma HepG2, breast adenocarcinoma MCF-7, and malignant melanoma A375 cells. In colon cancer cells, it was also shown that the growth inhibitory effect of prenylchalcone 2e was associated with the induction of cell cycle arrest, apoptosis, and increased protein expression levels of p53 transcriptional targets. Moreover, computational docking studies were performed in order to predict docking poses and residues involved in the MDM2-p53 potential interaction.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11