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Synthesis and molecular docking study of novel alizarin derivatives containing phosphoryl amino acid moiety as potential antitumor agents

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Abstract

Series of novel alizarin and phosphoryl amino acid scaffold (4a–4d, 8a–8d) were synthesized and evaluated for the suppression of cancer cell proliferation in vitro against MGC-803, HepG2, T24, NCI-H460, and SK-OV-3 cell lines by standard 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay compared with commercial anticancer drug doxorubicin. Interestingly, all newly synthesized compounds exhibited relatively high cytotoxicity compared with alizarin and low cytotoxicity against human normal liver cell line HL-7702 cells. Especially, compound 8d showed the best cytotoxicity against SK-OV-3 cells with IC50 7.09 µM, which was slightly worse than that of drug doxorubicin. The cell apoptosis-inducing activity of representative compound 8d in SK-OV-3 cells revealed that the anticancer activity of this compound depended on apoptosis of cancer cells via regulation of Bcl-2 family members, activation of caspase-9 and caspase-3. Cell cycle analysis confirmed that compound 8d mainly arrested SK-OV-3 cells in G2 stage. In addition, molecular docking studies were performed to position compound 8d into the telomerase (5CQG) active site to determine the probable binding model.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (No. 81260472, 21101035 and 21362002), Special Research Found for the Doctoral Program of Higher Education (NO. 20134504110002), the State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China (CMEMR2016-B06), a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (No. 1107047002).

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    Authors and Affiliations

    1. Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Southeast University, Nanjing, 211189, People’s Republic of China

      Ri-zhen Huang, Le Jin, Gui-yang Yao, Xiao-chao Huang & Zhi-Xin Liao

    2. State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Pharmaceutical Sciences of Guangxi Normal University, Guilin, 541004, People’s Republic of China

      Wei-long Dai & Heng-shan Wang

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    1. Ri-zhen Huang
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    Ri-zhen Huang and Le Jin have contributed equally to this work.

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    Huang, Rz., Jin, L., Yao, Gy. et al. Synthesis and molecular docking study of novel alizarin derivatives containing phosphoryl amino acid moiety as potential antitumor agents. Med Chem Res 26, 2363–2374 (2017). https://doi.org/10.1007/s00044-017-1938-2

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