Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 27, Issue 17, Pages 4066-4074Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2017.07.047
Keywords
Podophyllotoxin piperazine acetate ester; derivatives; Cytotoxicity; Cell cycle; Microtubule network; Modeling
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Funding
- Program for Changjiang Scholars and Innovative Research Team in University [IRT_14R27]
- National Natural Science Foundation of China [31470384, 31171161, 31670298]
- Fundamental Research Funds for the Central Universities [020814380002]
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In this paper, a series of podophyllotoxin piperazine acetate ester derivatives were synthesized and investigated due to their antiproliferation activity on different human cancer cell lines. Among the congeners, C5 manifested prominent cytotoxicity towards the cancer cells, without causing damage on the non-cancer cells through inhibiting tubulin assembly and having high selectively causing damage on the human breast (MCF-7) cell line (IC50 = 2.78 +/- 0.15 mu M). Treatments of MCF-7 cells with C5 resulted in cell cycle arrest in G2/M phase and microtubule network disruption. Moreover, regarding the expression of cell cycle relative proteins CDK1, a protein required for mitotic initiation was up-regulated. Besides, Cyclin A, Cyclin B1 and Cyclin D1 proteins were down-regulated. Meanwhile, it seems that the effect of C5 on MCF-7 cells apoptosis inducing was observed to be not obvious enough. In addition, docking analysis demonstrated that the congeners occupy the colchicine binding pocket of tubulin. 2017 Elsevier Ltd. All rights reserved.
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