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

We previously reported that chalcone CM-M345 (1) and diarylpentanoid BP-C4 (2) induced p53-dependent growth inhibitory activity in human cancer cells. Herein, CM-M345 (1) and BP-C4 (2) analogues were designed and synthesized in order to obtain more potent and selective compounds. Compounds 16, 17, 19, 20, and 22-24 caused pronounced in vitro growth inhibitory activity in HCT116 cells (0.09 < GI(50) < 3.10 mu M). Chemical optimization of CM-M345 (1) led to the identification of compound 36 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 BP-C4 (2) resulted in the discovery of compound 16 with more pronounced antiproliferative activity and being selective for HCT116 cells with p53, as well as 17 with enhanced antiproliferative activity against HCT116 cells and low toxicity to non-tumor cells. Compound 16 behaved as an inhibitor of p53-MDM2 interaction, and compound 17 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 16 and 17. Docking and molecular dynamics studies predicted that 16 could bind stably to the MDM2 binding pocket.

Automated summary

Chalcone CM-M345 and diarylpentanoid BP-C4 analogues were designed and synthesized. Compounds 16, 17, 19, 20, and 22-24 showed pronounced in vitro growth inhibitory activity in HCT116 cells. Compound 36 was identified with increased selectivity for HCT116 cells expressing wild-type p53, while compound 16 showed more pronounced antiproliferative activity and selectivity for HCT116 cells with p53. Compound 17 was shown to induce apoptosis and had low toxicity to non-tumor cells.