Design, synthesis and antitubulin activity of novel podophyllotoxin derivatives as potent anticancer agent

Abstract

Twenty novel podophyllotoxin derivatives(1―20) were designed and synthesized. The anti-proliferation activities of these compounds were evaluated against three human cancer cell lines(HepG2, Calu-1 and MCF-7) using podophyllotoxin and Combretastatin A4(CA-4) as positive controls. Among all the compounds, compound 2 displayed more significant anti-proliferation activities against MCF-7 and Calu-1 cell lines and showed lower toxicity towards non-cancer cells. Furthermore, the cell cycle and apoptosis analysis results revealed that compound 2 can cause cell arrest at G2/M phase, leading to cancer cell apoptosis. Meanwhile, it can also reduce the adhesive ability of Calu-1 cells to fibronectin and laminin. The docking simulation results demonstrated that compound 10 can nicely bind to the colchicine site of tubulin. The podophyllotoxin derivatives are worthy to be further investigated to obtain more potent anti-cancer drugs.

Keywords

Podophyllotoxin / Anticancer / Antitubulin / Cell adhesion

References

[1] Karikas G. A. J. Buon., 2010, 15(4): 627.

[2] Mishra B. B., Tiwari V. K. Eur. J. Med. Chem., 2011, 46: 4769.

[3] Zhang P. N., Li Z. F., Zhao C. Q. Nat. Prod. Res. Dev., 2004, 16(1): 80.

[4] Gordaliza M. Clin. Transl. Oncol., 2007, 9(12): 767.

[5] Shang H., Chen H., Zhao D. M., Tang X. W., Liu Y. F., Pan L., Cheng M. S. Arch. Pharm. Chem. Life Sci., 2012, 345(1): 43.

[6] Bohlin L., Rosen B. Drug Discov. Today, 1996, 1(8): 343.

[7] Kumar A., Kumar V., Alegria A. E., Malhotra S. V. Curr. Med. Chem., 2011, 18(25): 3853.

[8] Sang C. Y., Liu J. F., Qin W. W., Zhao J., Hui L., Jin Y. X., Chen S. W. Eur. J. Med. Chem., 2013, 70: 59.

[9] You Y. Curr. Pharm. Des., 2005, 11(13): 1695.

[10] Liu Y. Q., Yang L., Tian X. Curr. Bioact. Compd., 2007, 3(1): 37.

[11] Gordaliza M., Castro M. A. d., Corral J. M., Feliciano A. S. Curr. Pharm. Des., 2000, 6(18): 1811.

[12] Berkowitz D. B., Maeng J. H., Dantzig A. H., Shepard R. L., Norman B. H. J. Am. Chem. Soc., 1996, 118: 9426.

[13] Kamal A., Tamboli J. R., Nayak V. L., Adil S. F., Vishnuvardhan M. V., Ramakrishna S. Bioorg. Med. Chem., 2014, 22(9): 2714.

[14] Kamal A., Tamboli J. R., Vishnuvardhan M. V., Adil S. F., Nayak V. L. Bioorg. Med. Chem. Lett., 2013, 23: 273.

[15] Kamal A., Suresh P., Ramaiah M. J., Srinivasa Reddy T., Kapavarapu R. K., Rao B. N., Imthiajali S., Lakshminarayan R. T. Bioorg. Med. Chem., 2013, 21(17): 5198.

[16] Wang H. W., Nogales E. Nature, 2005, 435: 911.

[17] Gourley M., Williamson J. S. Curr. Pharm. Des., 2000, 6: 417.

[18] Lin C. M., Ho H. H., Pettit G. R., Hamel E. Biochemistry, 1989, 28(17): 6984.

[19] Pettit G. R., Singh S. B., Hamel E., Lin C. M., Alberts D. S. Experientia, 1989, 45(2): 209.

[20] Pettit G. R., Toki B., Herald D. L., Verdier-Pinard P., Boyd M. R., Hamel E., Pettit R. K. J. Med. Chem., 1998, 41(10): 1688.

[21] Nam N. H. Curr. Med. Chem., 2003, 10(17): 1697.

[22] Abad A., López Pérez J. L., del Olmo E., García-Fernández L. F., Francesch A., Trigili C., Barasoain I., Andreu J. M., Díaz J. F., San Feliciano A. J. Med. Chem., 2012, 55(15): 6724.

[23] Castro M. A., del Corral J. M. M., Gordaliza M., García P. A., Gómez-Zurita M. A., García-Grávalos M. D., de la Lglesia-Vicente J., Gajate C., An F. Y., Mollinedo F., San Feliciano A. J. Med. Chem., 2004, 47(5): 1214.

[24] Ettinger D. S., Finkelstein D. M., Ritch P. S., Lincoln S. T., Blum R. H. Lung Cancer, 2002, 37(3): 311.

[25] Che C., Yang G. Q., Thiot C., Lacoste M. C., Currie J. C., Demeule M., Regina A., Beliveau R., Castaigne J. P. J. Med. Chem., 2010, 53(7): 2814.

[26] Qian Y., Zhang H. J., Lv P. C., Zhu H. L. Bioorg. Med. Chem., 2010, 18(23): 8218.