The Conjugation of Paclitaxel with Chalcones for Enhancing Anti-tumor Activity.

introductionThe decreased anticancer activity of paclitaxel was associated with many factors. The inactivity of p53 was one of the important causes. Some chalcones and their derivatives were found to inhibit the MDM2-p53 interaction. Therefore, the conjugation of chalcones with paclitaxel might be an effective strategy for enhancing the antitumor activity of paclitaxel.

methodsHere, three novel chalones, compounds 1a, 1b, and 1c were first designed and synthesized, followed by the conjugation of them with paclitaxel to prepare compounds 2a, 2b, and 2c. The anti-tumor activity of the aforementioned three novel paclitaxel-chalcone conjugates was evaluated by the MTT method, mitochondrial membrane potential analysis, apoptosis assay, and molecular docking.

resultsThe MTT assay demonstrated that compound 2a exhibited superior cytotoxicity compared to 2b and 2c toward breast cancer MCF-7 cells and MDA-MB-231 cells, with the differential activity correlating with electronic effects of their chalcone substituents: compound 2a possessed two electron-withdrawing chlorine groups, compound 2b lacked substitution, and compound 2c featured an electron-donating morpholine. Compared to paclitaxel, compound 2a exhibited a 1.7-fold enhancement in cytotoxic activity against MCF-7 cells and a 2.5-fold increase in potency against MDA-MB-231 cells. Further investigation showed that compound 2a could effectively decrease the mitochondrial membrane potential and induce cell apoptosis. Computational docking studies showed compound 2a formed two hydrogen bonds and one π-H interaction with MDM2, with a docking score of -8.5317. DISCUSSION: Research findings demonstrate that the designed chalcone derivatives can effectively inhibit MDM2 activity, with the inhibitory potency closely associated with the substituents on the chalcone core. Notably, the introduction of chlorine substituents not only enhances the binding affinity to MDM2 but also improves the antitumor activity of its hybrid with paclitaxel. Molecular docking analysis reveals that the chlorine-substituted chalcone forms a π-H interaction with Gln72 of MDM2, a feature absent in the other two designed chalcone structures. Furthermore, the chlorine substituent may increase the lipophilicity of the hybrid, facilitating cellular uptake and thereby potentiating its anticancer efficacy.

conclusionThese findings indicated that the conjugation of paclitaxel with chalones might be an effective strategy for strengthening the anticancer activity of paclitaxel.