3-Arylideneindolin-2-ones as inhibitors of MDM2-p53 interaction

The easily available 3-(hetero)arylidene-oxindoles are a privileged scaffold for compounds endowed with a variety of biological properties, mainly antitumor, but also antirheumatic, antibacterial, antifungal, antiangiogenic, chemopreventive, antioxidative. Recently 3-arylidene-oxindoles have been found to inhibit the MDM2-p53 interaction.1 As the interaction between MDM2 and p53 represents a promising target for the development of novel anticancer drugs, we decided to investigate whether compounds with a 3-benzylidene-indolin-2-one scaffold could work as inhibitors of this interaction, by combining both biological assays and docking studies. Here we report the design, synthesis, evaluation of antiproliferative activity and p53 activation of a series of 3-arylidene-oxindoles. Computational studies were used to investigate the ability of our compounds to interact with the p53 binding pocket of MDM2. An induced fit docking (IFD)2 protocol was performed by using the 3LBL crystal structure. Our results demonstrate that Z-isomers are able to mimic the three hot spots residues of p53 occupying the hydrophobic pocket of Trp23 on MDM2. Most of the compounds exhibited a potent antiproliferative activity against IGROV-1 cells and a much lower inhibitory activity against IGROV-1/Pt1 subline lacking p53 function. The differential response of the two ovarian carcinoma cell lines was also reflected in the different susceptibility to apoptosis induced by cytotoxic concentrations (IC80)of the compounds. One of the most potent compounds, chosen to evaluate the therapeutic potential in the treatment of IGROV-1 as tumor xenograft, produced appreciable inhibition of tumor growth (around 65%). The effect was persistent at the end of treatment.