Title:The Conjugation of Paclitaxel with Chalcones for Enhancing Anti-tumor Activity
Volume: 22
Issue: 8
Author(s): Zurong Song and Tianchen Wu*
Affiliation:
- Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, 210022, China
Keywords:
Paclitaxel, chalone, conjugate, synthesis, anticancer; activity.
Abstract:
Introduction: The 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.
Methods: Here, 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.
Results: The 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.
Conclusion: These findings indicated that the conjugation of paclitaxel with chalones might be an
effective strategy for strengthening the anticancer activity of paclitaxel.
