Design of Podophyllotoxin-based Hybrid Compounds as Potential Anticancer Agents

Background: Cancer has been regarded as the leading cause of death worldwide. Identifying new anti-neoplastics with high potency and low toxicity is urgent. Objective: Podophyllotoxin-based hybrid compounds were synthesized by esterification and characterized using NMR and HR-MS. In vitro cytotoxicity and molecular mechanism studies were performed. Methods: Podophyllotoxin was hybridized with three selected known natural compounds via esterification to develop candidates with increased biological activity or decreased toxicity. The CCK-8 assay, cell cycle analysis, AO/EB staining, immunofluorescent analysis, and molecular modeling were used for investigation. Results: Compound B4 displayed potent anticancer effect on HepG2 and HSC-2 cell lines, with IC50 values of 0.809 ± 0.183 and 0.267 ± 0.038 μM, respectively. Furthermore, B4 exhibited less antiproliferative activity in 293T cells with an IC50 value of 2.303 ± 0.216 μM. In addition, B4 demonstrated strong induction of S phase arrest and apoptosis, as well as demolished the microtubules in HSC-2 cells. Molecular docking study revealed that B4 could bind into the colchicine site of β-tubulin, as well as the interface of the α/β-tubulin dimer. Conclusion: Hybrid B4 exhibited potential anticancer activity, and further investigations can help in identifying novel lead molecules.