Design of Podophyllotoxin-based Hybrid Compounds as Potential Anticancer Agents

Abstract

Cancer has been regarded as the leading cause of death worldwide. Identifying new anti-neoplastics with high potency and low toxicity is urgent. Podophyllotoxin-based hybrid compounds were synthesized by esterification and characterized using NMR and HR-MS. In vitro cytotoxicity and molecular mechanism studies were performed. 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. 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. Hybrid B4 exhibited potential anticancer activity, and further investigations can help in identifying novel lead molecules.