Summary: | We previously reported that chalcone <b>CM-M345</b> (<b>1</b>) and diarylpentanoid <b>BP-C4</b> (<b>2</b>) induced p53-dependent growth inhibitory activity in human cancer cells. Herein, <b>CM-M345</b> (<b>1</b>) and <b>BP-C4</b> (<b>2</b>) analogues were designed and synthesized in order to obtain more potent and selective compounds. Compounds <b>16</b>, <b>17</b>, <b>19</b>, <b>20</b>, and <b>22</b>–<b>24</b> caused pronounced in vitro growth inhibitory activity in HCT116 cells (0.09 < GI<sub>50</sub> < 3.10 μM). Chemical optimization of <b>CM-M345</b> (<b>1</b>) led to the identification of compound <b>36</b> 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 <b>BP-C4</b> (<b>2</b>) resulted in the discovery of compound <b>16</b> with more pronounced antiproliferative activity and being selective for HCT116 cells with p53, as well as <b>17</b> with enhanced antiproliferative activity against HCT116 cells and low toxicity to non-tumor cells. Compound <b>16</b> behaved as an inhibitor of p53–MDM2 interaction, and compound <b>17</b> was shown to induce apoptosis, associated with an increase in cleaved PARP and decreased levels of the anti-apoptotic protein Bcl-2<b>.</b> In silico studies allowed us to predict the druglikeness and ADMET properties for <b>16</b> and <b>17</b>. Docking and molecular dynamics studies predicted that <b>16</b> could bind stably to the MDM2 binding pocket.
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