3-Methyl-4,5-dihydro-oxepine, polyoxygenated seco-cyclohexenes and cyclohexenes from Uvaria flexuosa and their anti-inflammatory activity

doi:10.1016/j.phytochem.2015.12.013

Phytochemistry

Volume 122, February 2016, Pages 184-192

https://doi.org/10.1016/j.phytochem.2015.12.013 Get rights and content

Highlights

•
A rare 3-methyl-4,5-dihydro-oxepine derivative was isolated from Uvaria flexuosa.
•
Isolation of four seco-cyclohexenes with a characteristic skeleton from Uvaria sp.
•
Two cyclohexenes were isolated with promising antiinflammatory activity.
•
Benzyl alcohol benzoyl transferase is a key enzyme in the biosynthesis of these isolates.

Abstract

The phytochemical investigation of the methanolic extract of Uvaria flexuosa (Annonaceae) leaves led to the isolation of seven compounds including, 3-methyl-4,5-dihydro-oxepine (flexuvaroxepine A), four polyoxygenated seco-cyclohexene (flexuvarin A–D) and two polyoxygenated cyclohexene (flexuvarol A–B) derivatives, together with four known flavones. The structures of the isolated compounds were elucidated using different spectroscopic techniques. A plausible biogenetic route of the new compounds was discussed. The anti-inflammatory activity of the isolated compounds was evaluated by superoxide anion generation and elastase release assays. Among the tested compounds, flexuvarol B and chrysin showed the most potent anti-inflammatory effect by inhibiting superoxide anion generation and elastase release from human neutrophils in response to fMLP with IC₅₀ 2.25–5.55 μM. Moreover, 5-hydroxy-6,7-dimethoxy-flavone showed selective inhibitory activity on superoxide anion generation (IC₅₀ = 1.19 ± 0.34 μM).

Graphical abstract

3-Methyl-4,5-dihydro-oxepine (1), four polyoxygenated seco-cyclohexenes (2–5) and two polyoxygenated cyclohexenes (6–7), along with four known compounds, were isolated from Uvaria flexuosa.

Introduction

Uvaria is a large genus comprising of nearly 150 species and belongs to the Annonaceae family (Meade and Parnell, 2003). The plants of this genus are climbing or trailing shrubs, which are widely distributed in tropical Asia, Africa, and Australia. The name of the genus is derived from Latin “uva”, which means cluster or bunch of grapes. The edible fruits are of high nutritional and economic values. In traditional medicine, various species of Uvaria have been used for the treatment of rheumatism, bowel complaints, and eczema (Parmar et al., 1994).

Previous studies on Uvaria sp. have shown their richness in different groups of secondary metabolites including dihydrochalcones, flavonoids, and polyoxygenated cyclohexenes (El-Sohly et al., 1979, Hufford and Oguntimein, 1982, Nkunya et al., 1993, Okorie, 1977, Takeuchi et al., 2002). Among the isolated components from this genus, polyoxygenated cyclohexenes represented a unique class of metabolites which are rarely isolated from natural sources. They are also restricted to certain plants belonging to the Zingiberaceae, Piperaceae and Annonaceae. Important biological effects were reported for both Uvaria sp. extracts and their isolated compounds, including antitumor, anti-leukemic and antibiotic activities (Nkunya et al., 1987, Pancharoen et al., 1989, Taneja et al., 1991).

Uvaria flexuosa is distributed only in Cambodia and Vietnam. Previous reports on U. flexuosa have primarily focused on studying its phylogeny and morphological characteristics (Meade and Parnell, 2003). The important biological activities reported for the isolated secondary metabolites of Uvaria sp. as well as the lack of previous phytochemical studies on U. flexuosa encouraged the study of a detailed investigation on this species. In the current study, the analysis of the methanolic extract of U. flexuosa leaves resulted in isolation of seven new compounds, including 3-methyl-4,5-dihydro-oxepine (flexuvaroxepine A (1)), four polyoxygenated seco-cyclohexene (flexuvarin A–D (2–5)) and two polyoxygenated cyclohexene (flexuvarol A–B (6–7)) derivatives (Fig. 1). In addition, four known flavones, 6,7-di-O-methyl-baicalein (8) (Stierlea et al., 1988), chrysin (9) (Tuchinda et al., 1991), negletein (10) (Yang et al., 1996), and 6-hydroxy-5,7-dimethoxy-flavone (11) (Osorio-Olivares et al., 1999) were isolated. The close resemblance of the isolated structures to certain previously isolated anti-inflammatory compounds suggested the importance of evaluating the anti-inflammatory effect of the isolated products (Seangphakdee et al., 2013).

Section snippets

Results and discussion

Compound 1 was obtained as a viscous oil. Its molecular formula was deduced as C₁₈H₁₈O₇ by the analysis of its ¹³C NMR and HR-ESI-MS data, which indicated ten degrees of unsaturation. The UV spectrum exhibited absorption maxima at 243 and 273 nm. The IR spectrum indicated the presence of an ester carbonyl functionality (1742 cm⁻¹). The ¹H NMR spectrum showed; three olefinic protons at δ 5.03 (1H, ddd, J = 7.2, 6.6, 0.6 Hz, H-6), 6.41 (1H, d, J = 7.2 Hz, H-7), and 6.81 (1H, s, H-2); two acetoxy methines

Conclusion

In this study, one new 3-methyl-4,5-dihydro-oxepine (flexuvaroxepine A (1)), four new polyoxygenated seco-cyclohexene (flexuvarin A–D (2–5)), two new polyoxygenated cyclohexene (flexuvarol A–B (6–7)) derivatives and four known flavones (8–11) were isolated from the leaves of U. flexuosa. The structures of these compounds were identified by various spectroscopic techniques. The biogenetic pathway of compounds 1–7 was also proposed. The anti-inflammatory activity of the isolates was evaluated by

General experimental procedures

Optical rotations were measured with a JASCO P-1020 Polarimeter, whereas IR spectra were obtained on a PERKIN ELMER System 2000 FT-IR spectrometer. ¹H and ¹³C NMR spectra were recorded on Varian V NMR-600, Varian INOVA 400 spectrometers. Chemical shifts (δ) are reported in parts per million, and the coupling constants (J) are expressed in Hertz. LREIMS and LRESIMS were measured on a VG Biotech Quattro 5022 mass spectrometer. HR-ESI-MS data were collected using a Bruker Daltonics APEX II mass

Conflict of interest

The authors declare no conflict of interest.

Acknowledgments

This work was supported by the grants from the Ministry of Science and Technology (NSC 103-2911-I-002-303; MOST 104-2911-I-002-302; MOST 103-2325-B-039-008; MOST 103-2325-B-039-007-CC1), National Health Research Institutes (NHRI-EX103-10241BI), the grant from Chinese Medicine Research Center, China Medical University (the Ministry of Education, the Aim for the Top University Plan), the Excellence for Cancer Research Center Grant, the Ministry of Health and Welfare, Executive Yuan (

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¹: These authors contributed equally to this work.

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3-Methyl-4,5-dihydro-oxepine, polyoxygenated seco-cyclohexenes and cyclohexenes from Uvaria flexuosa and their anti-inflammatory activity

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusion

General experimental procedures

Conflict of interest

Acknowledgments

Free Radic. Biol. Med.

Bioorg. Chem.

Phytochemistry

Virus Res.

Biochem. Pharmacol.

Phytochemistry

Phytochemistry

Phytochemistry

Adv. Med. Sci.

Phytochemistry

Phytochemistry

Tetrahedron: Asymmetry

Aromatic constituents of Uvaria grandiflora

J. Nat. Prod.

Characterization of an acyltransferase capable of synthesizing benzylbenzoate and other volatile esters in flowers and damaged leaves of Clarkia breweri

Plant Physiol.

Two new C-benzylated flavanones from Uvaria chamae and 13C NMR analysis of flavanone methyl ethers

J. Nat. Prod.

Cytotoxic oxepinochromenone and flavonoids from the flower buds of Rosa rugosa

J. Nat. Prod.

Two new C-benzylated flavanones from Uvaria chamae and ¹³C NMR analysis of flavanone methyl ethers