The p53 protein is one of the most important tumor suppressors. In about half of human cancers retaining wild-type (wt) p53, its pathway is inactivated due to the overexpression of endogenous negative regulators, namely murine double minute 2 (MDM2) and X (MDMX). Therefore, the disruption of p53-MDM2/X interactions represent an efficient and selective therapeutic strategy against wt p53-expressing tumors.

Diarylpentanoids are a promising antitumor agents with two aromatic rings connected by a five-carbon bridge. Although the underlying molecular mechanism by which these compounds suppress cancer cell growth is still unclear, the interference with the p53 pathway has been described. However, the interference with p53-MDM2/X interactions was never explored.

Thus, in silico studies of a library of diarylpentanoids led us to the identification of potential new MDM2/X ligands. The diarylpentanoids with the best docking scores obeying the druglikeness and ADMET prediction properties were synthesized. Their antiproliferative activity on colon cancer HCT116 and fibroblasts HFF-1 cells was evaluated, being the most potent and selective compounds further studied to explore their effect as inhibitors of p53–MDM2/X interactions. BP-C4 was identified as potential dual inhibitor. Additionally, in absence of p53 and in cells expressing a mutant p53 form the growth inhibitory effect was significantly reduced. Furthermore, the growth inhibitory effect of BP-C4 was associated with induction of cell cycle arrest and apoptosis. Computational docking studies were performed in order to predict docking poses and residues involved in the inhibition of p53-MDM2/X interactions.

Acknowledgments
This research was partially supported by the Strategic Funding UIDB/04423/2020 and UIDP/04423/2020 (Group of Natural Products and Medicinal Chemistry, CIIMAR) and UIDB/50006/2020 (LAQV/REQUIMTE), through national funds provided by the FCT and ERDF, within the framework of the program PT2020 and the project PTDC/SAUPUB/28736/2017. This research was also supported by IINFACTS, grant number CHIRALBIOACTIVE‐PI‐3RL‐IINFACTS‐2019 and CHIRALSINTESE_APSFCT_IINFACTS_2021. Joana Moreira and Joana Almeida acknowledges their grants (SFRH/BD/135852/2018 and 2020.05026.BD, respectively).