Anti-inflammatory quinoline alkaloids from the root bark of Dictamnus dasycarpus

doi:10.1016/j.phytochem.2020.112260

Phytochemistry

Volume 172, April 2020, 112260

https://doi.org/10.1016/j.phytochem.2020.112260 Get rights and content

Highlights

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A rare type of dimeric furoquinoline alkaloid via [2 + 2] cyclization was isolated.
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A pair of dimeric furoquinoline alkaloid enantiomers were separated.
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Six undescribed quinoline alkaloids were isolated from Dictamnus dasycarpus.
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Three quinoline alkaloids exhibited strong NO inhibitory effects in LPS-induced BV-2 microglial cells.

Abstract

Six undescribed quinoline alkaloids, named dasycarines A–E, and 18 known ones were isolated from the root bark of Dictamnus dasycarpus. All the structures were elucidated on the basis of comprehensive analysis of UV, IR, NMR, and HRMS spectroscopic data, and the absolute configurations were assigned via comparison of the calculated and experimental ECD data. (+)-Dasycarine A (1a) and (−)-Dasycarine A (1b) are a pair of enantiomers of dimeric furoquinoline alkaloid, which are the first dimeric via [2 + 2] cycloaddition of furan. The structure and absolute configuration of (−)-dasycarine A was determined via X-ray crystallography. Additionally, all the isolated compounds were tested for their inhibitory effects on NO production stimulated by LPS in BV-2 microglial cells. Three compounds showed strong inhibition with IC₅₀ values below 5.0 μM; nine compounds exhibited inhibition with IC₅₀ values in the range of 7.8–28.4 μM. Furthermore, we demonstrated that preskimmianine suppressed the levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and nuclear factor kappa B (NF-κB) in LPS-induced BV-2 microglial cells.

Graphical abstract

Six undescribed quinoline alkaloids, including a pair of enantiomers of dimeric furoquinoline alkaloid, along with 18 known ones were isolated from the root bark of Dictamnus dasycarpus. Their anti-inflammatory activities were evaluated.

Introduction

The root bark of Dictamnus dasycarpus Turcz. (Rutaceae), known as “Baixianpi” in Chinese, is a traditional Chinese medicine for the treatment of skin inflammation, eczema, rubella, rheumatism, and gynecologic inflammation (China Pharmacopoeia Committee, 2015), mainly grows in northeast China and Inner Mongolia. Previous phytochemical studies have revealed quinoline alkaloids and limonoids are the main characteristic constituents of D. dasycarpus (Du et al., 2005; Zhao et al., 1998). These alkaloids in D. dasycarpus have been reported to show various bioactivity, such as anti-inflammatory (Yoon et al., 2012; Gao et al., 2019), anti-cancer (Varamini et al., 2009), hepatoprotective (Yang and Chen, 2008), and neuroprotective effect (Jeong et al., 2010). Last decade, there are few reports about phytochemical study of D. dasycarpus, meanwhile, the mechanism remains to be researched. So, we have carried out a phytochemical investigation to search for more bioactive constituents from D. dasycarpus. In our continuing effort, 24 quinoline alkaloids (Fig. 1), including six undescribed quinoline alkaloids (dasycarine A–E), were obtained from D. dasycarpus. Of these, (±)-dasycarine A is a rare type of dimeric furoquinoline alkaloid via [2 + 2] cyclization of furan. Herein, the isolation, structural elucidation, and biological evaluation on the anti-inflammatory of all the compounds are reported.

Section snippets

Structural elucidation

(±)-dasycarine A (1) was obtained as a white amorphous powder with the molecular formula C₂₄H₁₈N₂O₄ established by HRESIMS (m/z 399.1341 [M + H]⁺, calcd. for C₂₄H₁₉N₂O₄, 399.1345). Its UV spectrum showed absorptions at 218, 229 and 311 nm, suggesting the presence of a quinoline skeleton similar to dictamnine (Yang et al., 2011; Fauvel et al., 1981). A set of ortho-disubstituted phenyl protons [δ_H 8.11 (1H, d, J = 7.8 Hz, H-5), 7.74 (1H, d, J = 7.8 Hz, H-8), 7.66 (1H, t, J = 7.8 Hz, H-7) and

Conclusions

Six previously undescribed quinoline alkaloids, as well as 18 known analogues, were isolated and identified from the 95% aqueous EtOH of D. dasycarpus. The rare dimer (1) of dictamnine via [2 + 2] cycloaddition was reported for the first time here. Through biological screening, some of the isolated alkaloids showed NO inhibition, which supply the proof for the traditional use and reference for the future research and development of D. dasycarpus.

General experimental procedures

UV spectra were recorded on a Shimadzu UV-2450 spectrophotometer (Shimadzu Co., Tokyo, Japan). IR spectra were obtained on a Thermo Nicolet Nexus 470 FT-IR spectrometer (MA, USA). NMR spectra were recorded on a Varian INOVA-500 (Varian Co., USA) and a Bruker Avance-400 FT NMR spectrometer (Bruker Co., Switzerland), and the chemical shifts were referenced to the solvent residual peak. HRESIMS data were determined on a Waters Xevo G2 Q-TOF mass spectrometer (Waters Co., Milford, MA, USA). The

Declaration of competing interest

The authors declare no competing financial interest.

Acknowledgments

This work was financially supported by the National Key Technology R&D Programs “New Drug Innovation” of China (No. 2018ZX09711001-008-003), National Traditional Chinese Medicine Standardization Project (No. 2017-110108-83-03-001423) and National Key Research and Development Project (No. 2018YFC1707300). We also thank A/Prof. D.C Xiong for his kind help.

References (29)

W.E. Campbell et al.
Quinolinone alkaloids from an Agathosma species
Phytochemistry
(1990)
R.A. Corral et al.
New balfourodendron 4-quinolone alkaloids
Tetrahedron
(1973)
M.T. Fauvel et al.
Alkaloids and flavonoids of Melicope indica
Phytochemistry
(1981)
M.Y. Lv et al.
Medicinal uses, phytochemistry and pharmacology of the genus Dictamnus (Rutaceae)
J. Ethnopharmacol.
(2015)
R. Storer et al.
Constituents of the root of Dictamnus albus L
Tetrahedron
(1973)
J. Sun et al.
Degraded limonoids and quinoline alkaloids from Dictamnus angustifolius G. Don ex Sweet. and their anti-platelet aggregation activity
Fitoterapia
(2013)
J. Sun et al.
Quinoline alkaloids and sesquiterpenes from the roots of Dictamnus angustifolius
Biochem. Syst. Ecol.
(2013)
W.M. Zhao et al.
Antifungal alkaloids and limonoid derivatives from Dictamnus dasycarpus
Phytochemistry
(1998)
S.P. Mara et al.
Quinolone alkaloids from zanzboxylum acutifoliuiw
Phytochemistry
(1992)
I.S. Chen et al.
Quinoline alkaloids and other constituents of melicope semecarpifolia with antiplatelet aggregation activity
J. Nat. Prod.
(2001)

(2015)

G.M. Coppola et al.

¹³C NMR investigation of some hetero‐ring substituted 2‐ and 4‐quinolone systems

Magn. Reson. Chem.

(2005)

L.E. Cuca-Suarez et al.

Biological activity of secondary metabolites from peltostigma guatemalense

Nat. Prod. Res.

(2009)

L.E. Cuca-Suarez et al.

Quinoline alkaloids and friedelane-type triterpenes isolated from leaves and wood of Esenbeckia alata kunt (Rutaceae)

Quim. Nova

(2011)

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In this article, 26 compounds of substituted quinoline derivatives were synthesized and their α-glucosidase inhibition activity against the α-glucosidase enzyme was investigated. The screening results revealed that most of the synthesized substituted quinoline compounds demonstrated moderate to very good α-glucosidase inhibitory activity when compared to the first-line drug Acarbose (standard). The IC₅₀ values were obtained in the range of 21.71–375.00 µM. Amongst the substituted functionalized quinoline derivatives, compounds 10b, 10d, 11c-11d, 17b-17c, and 18c-18d displayed very promising results. The single crystal X-ray diffraction of compound 12 unambiguously confirmed its structure. This study has unravelled a new series of substituted quinoline derivatives as good inhibitors of α-glucosidase enzyme. All the active hits were docked in the active site of α-glucosidase to investigate their mode of binding. We conclude that the newly introduced substituents are important for interaction affecting as they demonstrate the potential of these compounds for α-glucosidase inhibitors.

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¹: These authors contributed equally.

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Anti-inflammatory quinoline alkaloids from the root bark of Dictamnus dasycarpus

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Structural elucidation

Conclusions

General experimental procedures

Declaration of competing interest

Acknowledgments

Phytochemistry

Tetrahedron

Phytochemistry

J. Ethnopharmacol.

Tetrahedron

Fitoterapia

Biochem. Syst. Ecol.

Phytochemistry

Quinolone alkaloids from zanzboxylum acutifoliuiw

Phytochemistry

Quinoline alkaloids and other constituents of melicope semecarpifolia with antiplatelet aggregation activity

J. Nat. Prod.

13C NMR investigation of some hetero‐ring substituted 2‐ and 4‐quinolone systems

Magn. Reson. Chem.

Biological activity of secondary metabolites from peltostigma guatemalense

Nat. Prod. Res.

Quinoline alkaloids and friedelane-type triterpenes isolated from leaves and wood of Esenbeckia alata kunt (Rutaceae)

Quim. Nova

¹³C NMR investigation of some hetero‐ring substituted 2‐ and 4‐quinolone systems