Abstract
Using matrine (1) as the lead compound, a series of new piperazinyl matrine derivatives were designed, synthesized and evaluated for their antitumor activities in vitro and in vivo. Structure activity relationship (SAR) analysis indicated that introduction of substituted piperazine on matrine might significantly enhance the antiproliferative activity. Moreover, types of substituents of piperazine exhibited great different effects on the antiproliferative activity of target compounds against Bel-7402 and RKO cell lines. The in vivo antitumor assay results revealed that some of the target derivatives possessed better therapeutic efficacy than matrine and low toxicity. More importantly, among the newly synthesized compounds, M16 and M26 possessed strong antitumor activity against the two cell lines. Moreover, six of the synthesized compounds M1, M3, M7, M10, M11 and M17 proved to be of much better therapeutic efficacy than matrine via in vivo antitumor assay. The study provides a theoretical basis for further structural optimizations and discovery of the antitumor pathways of this kind of compounds.
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Acknowledgements
We are grateful to Prof. Chen Rui, Faculty of Chinese Medicine Science, Guangxi University of Chinese Medicine for proofreading of the manuscript.
Author contributions
Y.X. and P.L. performed research and drafted the initial manuscript. H.R. revised and approved the manuscript. L.W. helped in biological activity. P.X modified the language. H.W. and S.Z. contributed the compounds synthesis. L.W. and J.J. designed the research.
Funding
This work was supported by the National Natural Science Foundation of China (21403225), the Innovation Project of Guangxi Graduate Education (YCBZ2019026), the high-level innovation team and outstanding scholar project of Guangxi institutions of higher education (guijiaoren (2014) 49 hao), Guangxi Natural Science Foundation (2017GXNSFBA198240) and the State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University (CMEMR2017-B14).
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Mice were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China). All protocols and care of the mice were performed in strict compliance with Guidelines for the Use of Laboratory Animals (National Research Council) and approved by the SPF Animal Laboratory of Guangxi University.
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Xu, Y., Liang, P., Rashid, H.u. et al. Design, synthesis, and biological evaluation of matrine derivatives possessing piperazine moiety as antitumor agents. Med Chem Res 28, 1618–1627 (2019). https://doi.org/10.1007/s00044-019-02398-2
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DOI: https://doi.org/10.1007/s00044-019-02398-2