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

Jun-Bo Gao; Xing-Jie Zhang; Rui-Han Zhang; Li-Li Zhu; De-Bing Pu; Xiao-Li Li; Hong-Lin Li; Min Xu; Wei-Lie Xiao

doi:10.1055/a-0598-4866

Planta Medica, Table of Contents

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

Authors

Jun-Bo Gao

¹State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China

⁵University of Chinese Academy of Sciences, Beijing, China
Xing-Jie Zhang

²Key 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

²Key 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

⁴State 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

²Key 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

²Key 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

⁴State 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

³Department of Pharmacology, School of Medicine, Southeast University, Nanjing, China
Wei-Lie Xiao

¹State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China

²Key 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

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

Full Text

References

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Supplementary Material

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