Design of Podophyllotoxin-based Hybrid Compounds as Potential Anticancer
Agents

Hezhen      Wang; Xun      Sun; Chunyong      Wei; Jing      Wang; Lei      Zhang

doi:10.2174/1570180820666230606161639

Abstract

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.

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DOI https://dx.doi.org/10.2174/1570180820666230606161639	Print ISSN 1570-1808
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Letters in Drug Design & Discovery

Design of Podophyllotoxin-based Hybrid Compounds as Potential Anticancer Agents

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