Hirsutalins I–M, eunicellin-based diterpenoids from the soft coral Cladiella hirsuta

doi:10.1016/j.tet.2013.01.015

Tetrahedron

Volume 69, Issue 10, 11 March 2013, Pages 2296-2301

https://doi.org/10.1016/j.tet.2013.01.015 Get rights and content

Abstract

New eunicellin-base diterpenoids, hirsutalins I–M (1–5), were isolated from the soft coral Cladiella hirsuta. Their structures were elucidated by spectroscopic methods, particularly in 1D and 2D NMR experiments. The absolute configuration of 2 was determined by Mosher's method. These compounds did not exhibit cytotoxicity toward a limited panel of cancer cell lines but showed nitric oxide inhibitory activity in LPS-stimulated RAW264.7 macrophage cells. Among them, compound 3 was found to possess the strongest NO inhibitory activity with an IC₅₀ value of 9.8 μg/mL. Furthermore, 3 was shown to significantly reduce the expression iNOS protein in the same cells.

Graphical abstract

New eunicellin-based diterpenoids, were isolated from the soft coral, Cladiella hirsuta.

Introduction

Previous reports on the chemical constituents of soft corals belonging to the genus Cladiella1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 have shown that eunicellin-based diterpenoids are major secondary metabolites in these marine organisms. During the course of our investigation into new natural substances from the soft coral Cladiella hirsuta, new eunicellin-type metabolites hirsutalins A–H,¹⁷ and several polyoxygenated steroids, hirsutosterols A–G,¹⁸ were isolated. In our continuing effort toward the discovery of new and bioactive substances from marine invertebrates, the chemical constituents of the soft coral C. hirsuta were further studied. This investigation again led to the isolation of five new eunicellin-based metabolites, hirsutalins I–M (1–5). The structures with relative configuration of compounds 1–5 were established by extensive spectroscopic analysis, including 2D NMR (¹H–¹H COSY, HSQC, HMBC, and NOESY) spectroscopy. The absolute configuration of 2 was further determined by Mosher's method. Cytotoxicity of metabolites 1–5 against a limited panel of human tumor cell lines including human liver carcinoma (Hep G2), human breast carcinoma (MDA-MB-231) and human lung carcinoma (A-549) and the anti-inflammatory activity of 1–5 to inhibit NO (nitric oxide) production and up-regulation of the pro-inflammatory iNOS (inducible nitric oxide synthase) in LPS (lipopolysaccharide)-stimulated RAW264.7 macrophage cells were studied.

Section snippets

Results and discussion

The frozen bodies of the octocoral C. hirsuta were minced and extracted exhaustively with acetone. The combined organic extract was concentrated to an aqueous suspension, which was partitioned between EtOAc and H₂O. The EtOAc-soluble fraction was concentrated under reduced pressure and the residue was repeatedly purified by chromatography to yield metabolites 1–5 (Scheme 1).

Hirsutalin I (1) was isolated as a colorless oil. The HRESIMS of 1 exhibited an [M+Na]⁺ peak at m/z 505.2780, which

General experimental procedures

Optical rotation was measured on a JASCO P-1020 polarimeter. IR spectra were recorded on a JASCO FT/IR-4100 infrared spectrophotometer. ESIMS spectra were obtained with a Bruker APEX II mass spectrometer. NMR spectra were recorded on a Varian 400 MR FT-NMR at 400 MHz for ¹H and 100 MHz for ¹³C. Silica gel (Merck, 230–400 mesh) was used for column chromatography. Precoated silica gel plates (Merck, Kieselgel 60F-254, 0.2 mm) were used for analytical TLC. High-performance liquid chromatography

Acknowledgements

Financial support awarded to J.-H.S. was provided by the National Science Council of Taiwan (NSC-100-2320-B-110-001-MY2), and the Ministry of Education of Taiwan (01C030205).

References and notes (29)

R. Kazlauskas et al.
Tetrahedron Lett.
(1977)
J.E. Hochlowski et al.
Tetrahedron Lett.
(1980)
Y. Uchio et al.
Tetrahedron Lett.
(1992)
Y. Uchio et al.
Tetrahedron Lett.
(1989)
M.J. Ortega et al.
Tetrahedron
(1993)
A.F. Ahmed et al.
Steroids
(2003)
H.-K. Kim et al.
Biochem. Pharmacol.
(1999)
Y.-H. Hsieh et al.
Phytomedicine
(2007)
H.M. Hassan et al.
J. Nat. Prod.
(2010)
D.E. Williams et al.
Aust. J. Chem.
(2010)

Y.-H. Chen et al.

Chem. Pharm. Bull.

(2011)

Y.-H. Chen et al.

Mar. Drugs

(2010)

A.F. Ahmed et al.

J. Nat. Prod.

(2005)

M.L. Ciavatta et al.

J. Nat. Prod.

(2011)

Cited by (21)

Coniferains A and B, new eunicellin-based diterpenoids from the octocoral Cladiella conifera (Tixier-Durivault, 1943)
2022, Phytochemistry Letters
Citation Excerpt :
Soft corals belonging to the genus Cladiella (Gray 1869, phylum Cnidaria, class Anthozoa, subclass Octocorallia, order Alcyonacea, suborder Alcyoniina, family Alcyoniidae), including C. australis (Ahmed et al., 2005), C. hirsuta (Chen et al., 2010, 2013; Huang et al., 2014, 2015), C. krempfi (Lee et al., 2013, 2014; Tai et al., 2011, 2013, 2014), C. tuberculosa (Peng et al., 2016), and Cladiella spp. (Chen et al., 2012, 2013, 2014a,b, 2019; Shih et al., 2013; Zhang et al., 2019a,b), collected from Formosan waters with a high level of biodiversity provided by convergence of the Kuroshio current and South China Sea surface current, were proven to be rich sources of eunicellin-based diterpenoids, a type of 2,11-cyclized cembranoids found solely in marine organisms.
Nine-Membered Rings
2021, Comprehensive Heterocyclic Chemistry IV
Diving into the world of marine 2,11-cyclized cembranoids: A summary of new compounds and their biological activities
2020, Natural Product Reports
Covering: 2010 to 2020
The class of 2,11-cyclized cembranoids is particularly widespread in marine Octocorallia, especially Alcyonacea and Gorgonacea, and has been extensively studied. Following a previous review published in 2010, the accumulated knowledge from the past decade will be presented here. All 2,11-cyclized cembranoids share a bicyclo[8.4.0]tetradecane core that is in most of the known compounds oxidatively modified to result in the 15-oxatricyclo[6.6.1.0^2,7]pentadecane system. Multiple further oxidation and acylation patterns can be observed, while halogenated compounds are surprisingly rare. One new sulfur-containing and a few seco-compounds have also been reported. The biosynthetic pathways to this fascinating class of natural products have not been studied to date, but a plausible biosynthetic hypothesis is presented that allows for a structured discussion of the compounds according to their carbon skeletons and oxidation patterns. Biological activities towards 2,11-cyclized diterpenes are also included.
An investigation on in vitro anti-inflammatory and antiproliferative potential of isolated Labdane diterpenoids from Andrographis paniculata (Burm. f.) wall. Ex nees: An important medicinal plant prescribed in Ayurveda
2019, European Journal of Integrative Medicine
Citation Excerpt :
Several marine drugs as, eunicellin-based diterpenes include krempfielins, hirsutalins, klymollins, klysimplexin, klysimplexin sulfoxide, simplexin, and cladieunicellin have been isolated and identified from soft corals belonging to the genera Cladiella +or Klyxum. These phytochemicals have shown the capacity to inhibit the upregulation of COX-2, or IL-6 proteins in RAW 246.7 macrophages stimulated with lipopolysaccharide [40,41]. However, multiple lines of evidence in vitro, in vivo, observational and clinical data now confirm that selective COX-2 inhibitors reduce prostaglandin production and the risk of colorectal, skin and other neoplasias.
The inflammatory response is a highly regulated process, and its dysregulation can lead to the establishment of chronic inflammation and in some cases, to death. Diterpenoids have found to be an important class of phytochemicals possessing anti-inflammatory potential.
In present study, some Labdane diterpenoids isolated from Andrographis paniculata like, Andrographolide (compound A); 14-deoxy-11,12-didehydroandrographolide (compound B); 14-Deoxyandrographolide (compound C) and 3,14- Dideoxyandrographolide (compound D) were evaluated for their cyclooxygenase inhibitory, antioxidant and anti-proliferative activity using different cancer cell lines.
The results obtained revealed that compound C has maximum inhibitory potential towards COX-2 (83.24%; IC₅₀ 9.0 μg/ml). The docking data was found to be in accordance with the in vitro experimental results, with compound C demonstrating the promising binding free energy (-8.1 Kcal/mol). The anti-proliferative data showed that all compounds had significant cytotoxicity towards selected (HCT-15, INT- 407 and HeLa-B75) cancer cell lines, while compounds also demonstrated effective antioxidant potential. The antioxidant profile reveals that, the compound C possess most promising SOR scavenging activity (91.41 ± 1.56%), while the lowest activity was recorded from compound D (16.30 ± 0.25). The results obtained by in silico molecular docking study are in accordance with the in vitro activities.
The isolated compounds showing promising anti-inflammatory and antiproliferative activity could be considered for acceleration in research for development of diterpenoids based anti-inflammatory agents.
Modular total syntheses of thymifodioic/incanic acids
2019, Arabian Journal of Chemistry
Citation Excerpt :
Diterpenes comprise four isoprene units, and they constitute a vast family of secondary metabolites with diverse molecular architecture. Isolation (Li et al., 2015; Huang et al., 2014; Chen et al., 2013), synthesis (Serra and Lissoni, 2015; Zheng et al., 2014; Ishihara et al., 2013), varied biological studies (He et al., 2015; Sun et al., 2013; Su et al., 2012), biotransformation (Rico-Martínez et al., 2014) and even computational predictions (Liu et al., 2015) related to diterpenes appear continuously in the bibliography, highlighting the interest of these compounds. Thymifodioic acids or incanic acids (1–4) (Fig. 1) are linear diterpenoids containing a furan unit and two α,β-unsaturated acids.
The first total synthesis of the bioactive natural product 2,6-(E,E)-thymifodioic acid, also called incanic acid, and its stereoisomers is described. An unified, iterative and modular strategy was envisioned, achieving the synthesis of the goals products after five reaction steps in an overall yield ranging from 8% to 16%. The key step is a non-expensive easy to perform Horner–Wadsworth–Emmons condensation.
Further new eunicellin-based diterpenoids from the Guangxi Weizhou soft coral Cladiella krempfi
2018, Fitoterapia
Citation Excerpt :
These marine natural products, characterized by a cladiellane-based diterpene skeleton and often a C-2, C-9 ether bridge generated tetrahydrofuran (THF) ring, have long been intriguing research subjects of both chemists and pharmacologists due to their complex/intriguing structural features and various promising bioactivities, e.g. antimitotic agent eleutherobin [12] and potent antileukemic compound sclerophytin A [13]. Soft corals of the genus Cladialla (Family Alcyoniidae), which are quite abundant in South China Sea, have been proven to be a rich source of tricyclic eunicellin-type diterpenes [4–9]. Several years ago, as part of our ongoing project to search for biologically active compounds, especially diterpenoids, from Chinese soft corals, we have reported the isolation and structural characterization of eight new eunicellin-based diterpenoids from C. krempfi collected off Weizhou Island of Guangxi Zhuang Autonomous Region, China [14,15].
Three new polyoxygenated diterpenes (1, 3 and 4) of eunicellin-type, namely, 8-n-butyryl-litophynol A, 6-keto-litophynol B and 6-epi-litophynol B, respectively, together with two related known ones (2 and 5), were isolated from the soft coral Cladiella krempfi collected off the Weizhou island, Guangxi Zhuang Autonomous Region, China. The structures of the new compounds were elucidated by extensive spectroscopic analysis and chemical correlation. In bioassay, all the new compounds displayed moderate anti-inflammatory effects.

View all citing articles on Scopus

View full text

Hirsutalins I–M, eunicellin-based diterpenoids from the soft coral Cladiella hirsuta

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

General experimental procedures

Acknowledgements

Tetrahedron Lett.

Tetrahedron Lett.

Tetrahedron Lett.

Tetrahedron Lett.

Tetrahedron

Steroids

Biochem. Pharmacol.

Phytomedicine

J. Nat. Prod.

Aust. J. Chem.

Chem. Pharm. Bull.

Mar. Drugs

J. Nat. Prod.

J. Nat. Prod.