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Lasiokaurin derivatives: synthesis, antimicrobial and antitumor biological evaluation, and apoptosis-inducing effects

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Abstract

Herein, a series of lasiokaurin derivatives were designed and synthesized. All the derivatives together with lasiokaurin and oridonin were tested for their antimicrobial and antiproliferative activity. Compound 16 showed the most promising antimicrobial activity with MICs of 2.0 and 1.0 μg/mL against Gram-Positive bacteria S. aureus and B. subtilis, respectively. All the synthetic lasiokaurin derivatives showed better antiproliferative activity than parent compound lasiokaurin 1. Compound 10 exhibited the strongest cytotoxicity with IC50 values of 0.47 and 0.20 μM against MGC-803 and CaEs-17 cells, accordingly. Moreover, it was shown to have potent antitumor activity in vivo in a murine model of MGC-803 gastric cancer. Preliminary SARs were also concluded based on obtained data. The apoptosis-inducing effects of 10 were further investigated using CaEs-17 cells. The results showed that lasiokaurin derivative 10 could induce apoptosis via mitochondria related pathway and arrest CaEs-17 cell cycle at S phase. Compound 10 could also affect apoptosis-related proteins that was up-regulation of CDK2 and down-regulation of ATM and cyclin A1.

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Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (81373280, 21502121), Project Funded by China Post Doctoral Science Foundation (2015M570258), Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy (KF-XY-201401) and Career Development Support Plan for Young and Middle-aged Teachers in Shenyang Pharmaceutical University.

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    Authors and Affiliations

    1. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical College, Xuzhou, 221004, China

      Da-hong Li & Xiao-ke Gu

    2. Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China

      Da-hong Li, Ping Hu, Chun-yan Fang, Shuang Tang, Xin-yu Wang, Xing-yan Sun, He Li & Ying Xu

    3. Department of Medicinal Chemistry and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China

      Sheng-tao Xu & Jin-yi Xu

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    Correspondence to Xiao-ke Gu or Jin-yi Xu.

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    Da-hong Li and Ping Hu contributed equally to this study.

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    Li, Dh., Hu, P., Xu, St. et al. Lasiokaurin derivatives: synthesis, antimicrobial and antitumor biological evaluation, and apoptosis-inducing effects. Arch. Pharm. Res. 40, 796–806 (2017). https://doi.org/10.1007/s12272-016-0867-9

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