Diarylpentanoids are chalcone analogues with two aromatic rings connected by a five-carbon bridge, showing a wide range of biological activities, being the in vitro growth inhibitory activity against cancer cells one of the most studied. However, the underlying mechanisms by which these compounds suppress cancer cell growth is still unclear. Our research group has reported several chalcones with notable antiproliferative activity in human cancer cells. Particularly, chalcone CM-M345 showed potent growth inhibitory activity against a panel of cancer cells, being this associated with the interference with the interaction between the tumor suppressor protein p53 and its endogenous negative regulator MDM2. In this communication, the design, synthesis, and biological evaluation of analogues of CM-M345 with diarylpentanoid scaffold showing promising antitumor activity are explored. From these studies new diarylpentanoids with promising antitumor effect through the interference with p53 pathway and mitosis have emerged. Our results show, for the first time, that exploration of diarylpentanoid scaffold can result in the discovery of new potential p53-MDM2/X dual inhibitors as well as promising antimitotic agents, which may be used as starting point for the discovery of new drug candidates for cancer therapy.