6
Bioorganic & Medicinal Chemistry Letters
Briefly, sixteen new podophyllotoxin derivatives
13. Shang, H.; Chen, H.; Zhao, D. M.; Tang, X. W.; Liu, Y. F.; Pan, L.;
Cheng, M. S. Arch. Pharm 2012 345, 43.
14. Xu, H.; Lv, M.; Tian, X. Curr. Med. Chem
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Ther Pat 2015 25, 1025.
containing piperazine ring, were synthesized and evaluated
for their activities against multi-cancer cells. Most of the
compounds could prevent the cancer cells proliferation and
displayed low cytotoxicity towards non-cancer cells. Among
them, C5 showed the most significant anti-cancer activity in
MCF-7 cells in MTT assay. In addition, C5 could apparently
block cell cycle at G2 phase in a time- and dose-dependent
manner. However, this compound exhibited non-significant
effect on the cells apoptosis. Besides, the western blot
results indicated that the compound could up-regulate the
expression of CDK1 protein and down-regulate the Cyclin A,
Cyclin B1 and Cyclin D1 proteins. Particularly, our results
demonstrate a prominent effect of C5 inducing cell cycle
arrest at G2/M phase. Also, the expression of cell cycle
proteins changes which may validate that microtubules are
highly crucial in the process of cell division25, When the
dynamic equilibrium blocks was disrupted, changes of
protein expression occurred. Moreover, based on molecular
modeling analysis, we can see that the compounds dock to
the colchcine binding site of tubulin and meanwhile, the
.
,
.
2009, 16, 327.
.
,
.
,
17. Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med. Chem
57, 5845.
. 2014,
18. Jida, M.; Soueidan, M.; Willand, N.; Agbossou-Niedercorn, F.;
Pelinski, L.; Laconde, G.; Deprez-Poulain, R.; Deprez, B. Tetrahedron
Lett. 2011, 52, 1705.
19. Cho, S. D.; Song, S. Y.; Kim, K. H.; Zhao, B. X.; Ahn, C.; Joo, W.
H.; Yoon, Y. J.; Falck, J. R.; Shin, D. S. B. Kor. Chem. Soc. 2004, 25,
415.
20. Wang, Y.; Ai, J.; Wang, Y.; Chen, Y.; Wang, L.; Liu, G.; Geng, M.;
Zhang, A. J. Med. Chem 2011 54, 2127.
.
,
21. Meher, C.; Rao, A.; Omar, M. Asian. J. Pharm. Sci. Res. 2013, 3, 43
22. Ibezim, E.; Duchowicz, P. R.; Ortiz, E. V.; Castro, E. A.
Chemometr. Intell. Lab. 2012, 110, 81.
23. Chetan, B.; Bunha, M.; Jagrat, M.; Sinha, B. N.; Saiko, P.; Graser,
G.; Szekeres, T.; Raman, G.; Rajendran, P.; Moorthy, D.; Basu, A.;
confocal microscopy assay revealed that the compound C5
which was just like the colchicine, can inhibit the tubulin
polymerization. As a result, these experiments proved C5
could be a potential anti-cancer candidate.
,
Jayaprakash, V. Bioorg. Med. Chem. lett
24. Akkoc, M. K.; Yuksel, M. Y.; Durmaz, I.; Atalay, R. C. Turk. J.
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Acknowledgements
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).
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Figure and table captions:
Table 1 Chemical structures of C1-C16.
.
,
Table 2 The cytotoxicity of compound C1
-C16 against a panel of human
cancer cell lines and one non-cancer cell line
.
,
Fig. 1 Chemical structures of podophyllotoxin derivatives
.
, 16, 89.
Fig. 2 Effects of different concentrations of compound C5 and
podophyllotoxin on the cell cycle distribution of MCF-7 cells. (A) Cells
were treated with 0, 0.3, 0.6, 0.9 µM podophyllotoxin for 12 h. (B) Cells
were treated with 0, 0.3, 0.6, 0.9 µM C5 for 12 h. Images are
.
,
.
2012, 75, 311.
.
,
representative of three independent experiments. (G1 phase, green; S
phase, yellow and G2/M phase, blue). Data are mean S.E.M. of three
independent experiments. (*P < 0.05, **P < 0.01 compared to control).
Fig. 3 Effects of compound C5 and podophyllotoxin on the cell cycle
distribution of MCF-7 cells for different time. (A) Cells were treated with 0.6
µM podophyllotoxin for 0, 4, 8, 12, 16 h. (B) Cells were treated with 0.6 µM
C5 for 0, 4, 8, 12, 16 h. Images are representative of three independent
experiments. (G1 phase, green; S phase, yellow and G2/M phase, blue). Data
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2013, 68, 47.
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