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Synthesis and evaluation as potential antitumor agents of novel ursolic acid derivatives

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Abstract

Novel ursolic acid derivatives were synthesized, and their structures were confirmed by MS, IR, 1H NMR and 13C NMR spectral analysis. In vitro antitumor activities of these compounds against MGC-803 (gastric cancer cell) and Bcap-37 (breast cancer cell) human cancer cell lines were evaluated by MTT assay. The pharmacological screening results revealed that many derivatives exhibited moderate to high activities against the tested cell lines, and that most demonstrated more potent inhibitory activities than that of ursolic acid. Preliminarily mechanism study of representative compound 3h were carried out by acridine orange/ethidium bromide staining, Hoechst 33258 staining, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling assay, and flow cytometry which indicated that compound 3h can induce cell apoptosis of MGC-803 cells, and the apoptosis ratio reached 34.59 % after 36 h treatment at 10 μM.

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Abbreviations

ADM:

Adriamycin

AO/EB:

Acridine orange/ethidium bromide

13C NMR:

13C Nuclear magnetic resonance

DMF:

N,N-dimethylformamide

DMSO:

Dimethyl sulfoxide

EDCI:

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

HCPT:

10-Hydroxyl camptothecine

HOBt:

1-Hydroxybenzotriazole

1H NMR:

Proton nuclear magnetic resonance

IR:

Infra-red

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

TUNEL:

Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling

UA:

Ursolic acid

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Acknowledgments

The authors wish to thank the Key Technologies R&D Program (2014BAD23B01), National Nature Science Foundation of China (21372052, 21462012), Research Project of Chinese Ministry of Education (213033A), Guizhou Province S&T Program ([2012]6012, [2015]35) for the financial support.

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    Authors and Affiliations

    1. State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang, 550025, China

      Ming-Chuan Liu, Sheng-Jie Yang, Lin-Hong Jin, De-Yu Hu, Wei Xue & Song Yang

    2. Research Institute, Sinphar Tian-Li Pharmaceutical Co., Ltd, Hangzhou, 311100, China

      Ming-Chuan Liu & Sheng-Jie Yang

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    1. Ming-Chuan Liu
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    Correspondence to Song Yang.

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    Ming-Chuan Liu and Sheng-Jie Yang contributed equally to this work.

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    Liu, MC., Yang, SJ., Jin, LH. et al. Synthesis and evaluation as potential antitumor agents of novel ursolic acid derivatives. Med Chem Res 25, 2267–2279 (2016). https://doi.org/10.1007/s00044-016-1680-1

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    • DOI: https://doi.org/10.1007/s00044-016-1680-1

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