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Planta Med 2018; 84(14): 1013-1021
DOI: 10.1055/a-0598-4866
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

In Vitro Human Dihydroorotate Dehydrogenase Inhibitory, Anti-inflammatory and Cytotoxic Activities of Alkaloids from the Seeds of Nigella glandulifera

Jun-Bo Gao
1   State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China
5   University of Chinese Academy of Sciences, Beijing, China
,
Xing-Jie Zhang
2   Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; School of Chemical Science and Technology; and State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming, China
,
Rui-Han Zhang
2   Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; School of Chemical Science and Technology; and State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming, China
,
Li-Li Zhu
4   State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
,
De-Bing Pu
2   Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; School of Chemical Science and Technology; and State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming, China
,
Xiao-Li Li
2   Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; School of Chemical Science and Technology; and State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming, China
,
Hong-Lin Li
4   State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
,
Min Xu
3   Department of Pharmacology, School of Medicine, Southeast University, Nanjing, China
,
Wei-Lie Xiao
1   State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China
2   Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; School of Chemical Science and Technology; and State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming, China
› Author Affiliations
Further Information

Publication History

received 29 November 2017
revised 16 March 2018

accepted 23 March 2018

Publication Date:
05 April 2018 (online)

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Abstract

Four new dolabellane-type diterpene alkaloids, glandulamines A – D (1 – 4), together with twelve known compounds (5 – 16), were isolated from the seeds of Nigella glandulifera using repeated column chromatography and semipreparative HPLC. The structures of 1 – 16 were elucidated based on NMR data analysis, HRMS experiments and other spectroscopic interpretations. The absolute configuration of 5 was determined by single-crystal X-ray diffraction data for the first time. Compounds 10 and 12 showed human dihydroorotate dehydrogenase inhibitory activity with IC50 values of 61.1 ± 5.3 and 45.9 ± 3.0 µM, respectively. Molecular docking of the active compound 12 and positive control teriflunomide on the inhibitor-binding site of human dihydroorotate dehydrogenase was subsequently performed to visualize the interaction pattern. In addition, compounds 8 and 10 exhibited inhibitory effects against lipopolysaccharide-induced nitric oxide production with inhibition rates of 61 and 41%, respectively, at the concentration of 10 µM. Compounds 9 and 12 showed cytotoxic activities with cell viability varying from 29 ~ 57% at 100 µM against T98G, U87, U251, and GL261 glioma cancer cell lines. These data provide new insights on the pharmacologically active compounds of this plant widely used in folk medicine.

Key words

dolabellane-type diterpene alkaloids - Ranunculaceae - Nigella glandulifera - human dihydroorotate dehydrogenase - lipopolysaccharide - nitric oxide production - cytotoxic activity

Supporting Information

    1H, 13C-NMR, DEPT, HSQC, HMBC, 1H-1H COSY, ROESY, HRMS, IR, and UV spectra of compounds 1 – 4, the crystal structure data of compound 5, numbering of compounds 11 to 16, and dose-response inhibitory activity of compounds 7, 10, and 12 against hDHODH are available as Supporting Information.

  • Supporting Information
 

  • References

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