Design, synthesis and anti-cancer evaluation of novel podophyllotoxin derivatives as potent tubulin-targeting agents
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A series of podophyllotoxin derivatives (M1–M16) that were selectively acylated by various phenoxy acids at the C-4 position of podophyllotoxin were synthesized, and their biological activities were also evaluated. Among them, compound M4 showed the most potent anti-cancer activity against HeLa cells with an IC50 value of 1.64 ± 0.41 μM. Additionally, flow cytometry analysis results indicated that it could cause a remarkable cell cycle arrest at G2/M phase, but the effect on apoptosis inducing was not significant. Moreover, the expression of cell cycle relative protein CDK1 was up regulated while cyclin B1 and Cdc25C, two proteins required for mitotic initiation were down regulated. Furthermore, the confocal assay and extracellular polymerized tubulin expression analysis also demonstrated that M4 was a potent tubulin polymerization inhibitor and the effect was comparable to that of colchicine. Finally, docking simulation results showed that M4 could nicely bind to the colchicine binding site of tubulin which further comfirmed the tubulin inhibiton activity of M4.
KeywordsAnti-cancer Podophyllotoxin Phenoxy acid Anti-tubulin Cell cycle
The authors are grateful to the Program for Changjiang Scholars and Innovative Research Team in University (IRT_14R27), the National Natural Science Foundation of China (31470384, 31171161, and 31670298), and the Fundamental Research Funds for the Central Universities (020814380002).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
- Holthuis JJM (1988) Etoposide and teniposide. Int J Clin Pharm 10:101–116Google Scholar
- Kamal A, Reddy MK, Shaik TB, Rajender, Srikanth YV, Reddy VS, Kumar GB, Kalivendi SV (2012) Synthesis of terphenyl benzimidazoles as tubulin polymerization inhibitors. Chem Inform 50:9–17Google Scholar
- Mokale SN, Sanap PT, Shinde DB (2010) Synthesis and hypolipidemic activity of novel 2-(4-(2-substituted aminothiazole-4-yl) phenoxy) acetic acid derivatives. Chem Inform 45:3096–3100Google Scholar
- Zuo D, Guo D, Jiang X, Guan Q, Qi H, Xu J, Li Z, Yang F, Zhang W, Wu Y (2014) 3-(3-hydroxy-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)- 1,2,5-selenadiazole (G-1103), a novel combretastatin A-4 analog, induces G2/M arrest and apoptosis by disrupting tubulin polymerization in human cervical HeLa cells and fibrosarcoma HT-1080 cells. Chem Biol Interact 227C:7–17Google Scholar