Structure-Activity Relationship Studies of Chalcones and Diarylpentanoids with Antitumor Activity: Potency and Selectivity Optimization.

We previously reported that chalcone () and diarylpentanoid () induced p53-dependent growth inhibitory activity in human cancer cells. Herein, () and () analogues were designed and synthesized in order to obtain more potent and selective compounds. Compounds , , , , and - caused pronounced in vitro growth inhibitory activity in HCT116 cells (0.09 < GI < 3.10 μM). Chemical optimization of () led to the identification of compound with increased selectivity for HCT116 cells expressing wild-type p53 compared to its p53-null isogenic derivative and low toxicity to non-tumor HFF-1 cells. The molecular modification of () resulted in the discovery of compound with more pronounced antiproliferative activity and being selective for HCT116 cells with p53, as well as with enhanced antiproliferative activity against HCT116 cells and low toxicity to non-tumor cells. Compound behaved as an inhibitor of p53-MDM2 interaction, and compound was shown to induce apoptosis, associated with an increase in cleaved PARP and decreased levels of the anti-apoptotic protein Bcl-2 In silico studies allowed us to predict the druglikeness and ADMET properties for and . Docking and molecular dynamics studies predicted that could bind stably to the MDM2 binding pocket.