Ecdysones from Zoanthus spp. with inhibitory activity against dengue virus 2

doi:10.1016/j.bmcl.2016.03.029

Bioorganic & Medicinal Chemistry Letters

Volume 26, Issue 9, 1 May 2016, Pages 2344-2348

https://doi.org/10.1016/j.bmcl.2016.03.029 Get rights and content

Abstract

Bioassay-guided fractionation of an ethanolic extract of Zoanthus spp. collected in Taiwan has resulted in the isolation of one new ecdysone, zoanthone A (1), along with thirteen known compounds (2–14). The structures of these compounds were determined by spectroscopic methods, especially 2D NMR analyses. The in vitro antiviral activities of all isolated ecdysones (1–14) against dengue virus type 2 (DENV-2) were evaluated using DENV infectious system. New compound (1) exhibited potent antiviral activity (EC₅₀ = 19.61 ± 2.46 μM) with a selectivity index (CC₅₀/EC₅₀) value of 36.7. The structure–activity relationships of isolated ecdysones against DENV-2 were concluded. Molecular docking information of 3 and NS5 polymerase was performed either.

Graphical abstract

Section snippets

Acknowledgments

This work was supported by grants from Ministry of Science and Technology of Taiwan (MOST103-2628-B-037-001-MY3 award to Y.-B.C.; MOST 103-2320-B-037-005-MY2 award to F.-R.C.), National Health Research Institutes (NHRI-EX103-10241BI), and in part from the grant from Chinese Medicine Research Center, China Medical University (the ministry of education, the Aim for the Top University Plan). This study is also supported partially by Kaohsiung Medical University (Aim for the Top Universities Grant,

References and notes (34)

A.D. Davidson
Adv. Virus Res.
(2009)
M. Ackermann et al.
J. Biol. Chem.
(2001)
B.H. Tan et al.
Virology
(1996)
A.H. Daranas et al.
Tetrahedron
(1998)
A.H. Daranas et al.
Tetrahedron
(1999)
Y.B. Cheng et al.
Tetrahedron Lett.
(2014)
A. Guerriero et al.
Comp. Biochem. Physiol.
(1985)
A. Suksamrarn et al.
Tetrahedron
(1995)
A. Suksamrarn et al.
Tetrahedron
(1999)
H. Malet et al.
J. Biol. Chem.
(2007)

M.P. Egloff et al.

EMBO J.

(2002)

D. Ray et al.

J. Virol.

(2006)

U.V. Babu et al.

Indian J. Chem. B

(1996)

A. Suksamrarn et al.

J. Nat. Prod.

(2002)

C.B. Rao et al.

J. Am. Chem. Soc.

(1984)

C.B. Rao et al.

J. Org. Chem.

(1985)

S. Fukuzawa et al.

Heterocycl. Commun.

(1995)

Cited by (25)

A comprehensive review of Pfaffia glomerata botany, ethnopharmacology, phytochemistry, biological activities, and biotechnology
2024, Journal of Ethnopharmacology
Pfaffia glomerata (Spreng.) Pedersen, Amaranthaceae, is found in South America, mainly in Brazil, where it is considered a species of great medicinal interest owing to its popular use as a tonic, aphrodisiac, anti-inflammatory, and analgesic. These properties can be attributed to the presence of the phytosteroid, 20-Hydroxyecdysone (β-ecdysone), the main compound found in its roots.
This review aims to provide information about the botanical characteristics, ethnomedicinal uses, the phytochemistry, the biological activities, and the biotechnology of P. glomerata, an important species to local communities and groups researching medicinal plants of South America.
The information available on P. glomerata was collected from scientific databases (ScienceDirect, PubMed/MEDLINE, SciELO, and Scopus) until June 7, 2023, using the search terms “Pfaffia glomerata”, “Pfaffia glomerata (Spreng.) Pedersen”, and “Brazilian ginseng”. The review includes studies that evaluated the botanical, ethnopharmacological, and phytochemical aspects, biological properties, nutraceutical uses, and the application of biotechnology for improving the biosynthesis of metabolites of interest.
A total of 207 studies were identified, with 81 articles read in full. Seventy-six studies were included for qualitative synthesis. Overall, 40 compounds belonging to different classes are presented in this review, including ecdysteroids, triterpenes, saponins, flavonoids, anthraquinones, tannins, coumarins, alkaloids, and polysaccharides. Among them, flavonoids, anthraquinones, tannins, coumarins, and alkaloids were only putatively identified. β-Ecdysone, triterpenes, saponins, and polysaccharides are the chemical components most frequently identified and isolated from P. glomerata and possibly responsible for ethnopharmacological use and the biological activities of this species, with important in vitro and in vivo activities, such as anti-inflammatory, antidepressant, aphrodisiac, analgesic, gastroprotective, antioxidant, and prebiotic.
This review summarizes discussions about the P. glomerata species, highlighting its ethnopharmacological, chemical, biotechnological, and nutraceutical importance. New scientific studies on this species are encouraged in the search for new therapeutic molecules with pharmaceutical potential and nutraceutical applications.
Ecdysteroids as defensive chemicals
2022, Advances in Insect Physiology
Citation Excerpt :
Eight of the 14 ecdysteroids isolated from Taiwanese sea anemones (Zooanthus spp.) were found to possess antiviral activity, with EC50s in the μM range, against dengue virus type 2, with AjuC having the highest activity (EC50 = 10 μM). The data permitted a preliminary SAR and docking studies in silico suggested that AjuC interacts with the DENV NS5 polymerase to arrest RNA replication (Cheng et al., 2016). Various ecdysteroids have been assessed against a range of Gram-positive and Gram-negative bacteria.
Ecdysteroids are best known as the steroid hormones of insects and other arthropods, where they are involved in the regulation of moulting, development and reproduction, but, in certain specific cases, they are present in much higher amounts as components of defensive secretions which serve to deter predators. Further, a wide range of ecdysteroid analogues are present in a significant proportion of plant and algal species (phytoecdysteroids) and some fungal species (mycoecdysteroids). The purpose of phytoecdysteroids seems to be to reduce invertebrate predation, either as antifeedants acting on taste receptors, or as endocrine disruptors acting through intracellular ecdysteroid receptors. While many invertebrate species are very sensitive to ingested ecdysteroids, others have developed very efficient avoidance or detoxification strategies, which allow them to evade the detrimental consequences of ecdysteroids in the diet. The purpose of this review is to assess the evidence for the roles of ecdysteroids as defence compounds, identify gaps in our knowledge and indicate prospects for future research.
Natural products for controlling dengue and its vectors
2022, Studies in Natural Products Chemistry
Citation Excerpt :
From the ethanol extract of the marine organism, Zoanthus sp., zoanthone A, and ajugasterone C compounds (Fig. 12.8) were isolated and screened against DENV-2, where these demonstrated an EC50 value of 19.6 and 10.1 μM, respectively. Also, the SI value for zoanthone A was 36.7 concerning Huh-7 cells [50]. In addition to these compounds, 12 other structurally related substances were isolated, in which it was demonstrated that the most active compounds have a hydroxyl group at C-2 or C-11.
Mosquitoes are estimated to be the deadliest living beings globally, mediating a million deaths worldwide. One of the diseases that mosquitoes can transmit is dengue fever, caused by the dengue virus, in which the species Aedes aegypti and Aedes albopictus are involved. Currently, dengue fever treatment mainly controls symptoms since there are still no licensed vaccines and/or approved drugs to treat this infectious disease. The products of natural origin, obtained from plants, microorganisms, and animals, have served as a basis for developing active substances against several diseases, including those resistant to conventional treatments. Besides, they provide us with a variety of molecular scaffolds beyond the developmental capabilities of synthetic medicinal chemists, serving as a source of constant inspiration for the development of new drugs. Phenolic compounds, flavonoids, peptides, alkaloids, and terpenes have been shown to inhibit essential viral replication processes, showing promise for dengue treatment. Other compounds still have the potential to control vector proliferation, such as simple aromatic compounds, lactones, terpenes, steroids, alkaloids, naphthoquinones, and phenylpropanoid coumarins, flavonoids, and lignans, acting both against the adult vector and against its larvae, and even their eggs. Notwithstanding these facts, we propose with this chapter a review of scientific studies that deal with the obtaining of useful substances produced by nature and/or inspired by nature for the control of the vector and treatment of the disease, focusing on the existing relationships between the molecular scaffolds and their biological activities.
Insights on Dengue and Zika NS5 RNA-dependent RNA polymerase (RdRp) inhibitors
2021, European Journal of Medicinal Chemistry
Citation Excerpt :
Furthermore, andrographolide (19) performs hydrogen-bonding interactions with Tyr89, Met116, and Ser128 residues, which are possibly associated with its activity [148]. Cheng et al. performed a study involving ethanolic extracts of sea anemone Zoanthus spp., in which 14 new ecdysones were isolated and evaluated against infected cells with DENV-2 [149]. Among this chemical class, ecdysone analog (20) (Fig. 9) exhibited an EC50 value of 10.05 μM, with CC50 and SI values of >700 μM and >69.7, respectively.
Over recent years, many outbreaks caused by (re)emerging RNA viruses have been reported worldwide, including life-threatening Flaviviruses, such as Dengue (DENV) and Zika (ZIKV). Currently, there is only one licensed vaccine against Dengue, Dengvaxia®. However, its administration is not recommended for children under nine years. Still, there are no specific inhibitors available to treat these infectious diseases. Among the flaviviral proteins, NS5 RNA-dependent RNA polymerase (RdRp) is a metalloenzyme essential for viral replication, suggesting that it is a promising macromolecular target since it has no human homolog. Nowadays, several NS5 RdRp inhibitors have been reported, while none inhibitors are currently in clinical development. In this context, this review constitutes a comprehensive work focused on RdRp inhibitors from natural, synthetic, and even repurposing sources. Furthermore, their main aspects associated with the structure-activity relationship (SAR), proposed mechanisms of action, computational studies, and other topics will be discussed in detail.
Adventitious root culture of Pfaffia glomerata (Spreng.) Pedersen in a roller bottle system: An alternative source of β-ecdysone
2021, Phytochemistry Letters
Citation Excerpt :
There are also studies showing the effect of P. glomerata as an analgesic, anti-inflammatory, anti-obesity, anti-diabetic, central nervous system depressant agent, leishmanicidal, and prebiotic agent (Sanches et al., 2001; Neto et al., 2004; 2005 Caleffi et al., 2015; Fortini et al., 2020). β-ecdysone has many potential applications in the pharmaceutical industry, due to its immunomodulatory, hepatoprotective, antiarrhythmic and cholesterol-lowering properties, as well as its anti-diabetic activity and its ability to regulate calcium mobilization and homeostasis (Kutepova et al., 2001; Cheng et al., 2016; Wang et al., 2016; Chakraborty and Basu, 2017; Bhardwaj et al., 2019). In the cosmetics industry, formulations containing β-ecdysone act as humectants (Iarema et al., 2012).
β-ecdysone is the main compound of commercial interest produced by the roots of Pfaffia glomerata (Spreng.) Pedersen, and is used in herbal medicines and dietary supplements. In-vitro root culture facilitates the continuous production of high-quality compounds, and uses sustainable production techniques. Adventitious roots of P. glomerata were cultivated in a roller bottle system and an orbital gyratory system, both in the absence of light. The quantification of β-ecdysone by Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC–MS/MS) revealed that the highest accumulation of metabolites occurred after 8 weeks in the roller bottle culture system, wherein 1.81 μg of β-ecdysone was recovered from 30 mg of dry root. These results suggest that adventitious root culture in-vitro may be an alternative strategy for β-ecdysone production, and demonstrates the potential use of bioreactors for practical applications.
Serotonin and dopamine derivatives from the Papua New Guinea zoantharian Zoanthus cf. sansibaricus
2020, Phytochemistry Letters
Citation Excerpt :
In our continued interest for the chemical diversity of zoantharians, a preliminary UHPLC-HRMS analysis of the aqueous/methanolic extract of Zoanthus cf. sansibaricus collected off the coast of PNG revealed the presence of unknown masses and characteristic isotopic patterns of monobrominated compounds. Herein, we report the isolation and structure elucidation of three serotonin derivatives 1–3 and one dopamine analogue 4 together with the known ecdysteroids ajugasterone C (5) (Suksamrarn et al., 2002); turkesterone (6) (Cheng et al., 2016); and 3-norpseudozoanthoxanthin (7) (Cariello et al., 1979) (Fig. 1). This is the first chemical study of Z. cf. sansibaricus and the first report of serotonin and dopamine analogues and zoanthoxanthin derivatives from a species of the genus Zoanthus.
In our continuous search for bioactive natural products from marine zoantharians, three serotonin derivatives 1-3 and one dopamine analogue 4 together with the known ecdysteroids ajugasterone C (5) and turkesterone (6) and zoanthoxanthin derivative 3-norpseudozoanthoxanthin (7) were isolated from Zoanthus cf. sansibaricus collected off the coast of Papua New Guinea. The structures of these alkaloids were elucidated through spectroscopic analyses including 1D and 2D NMR experiments and HRESIMS data. This is the first report of serotonin and dopamine derived alkaloids from species of the genus Zoanthus. Compounds 1-3 demonstrated moderate bactericidal activity against S. aureus NCTC 7447 with an IC₅₀ value of 83.3, 41.9 and 37.4 μM.

View all citing articles on Scopus

^†: These authors contributed equally to this work.

View full text

Ecdysones from Zoanthus spp. with inhibitory activity against dengue virus 2

Abstract

Graphical abstract

Section snippets

Acknowledgments

Adv. Virus Res.

J. Biol. Chem.

Virology

Tetrahedron

Tetrahedron

Tetrahedron Lett.

Comp. Biochem. Physiol.

Tetrahedron

Tetrahedron

J. Biol. Chem.

EMBO J.

J. Virol.

Indian J. Chem. B

J. Nat. Prod.

J. Am. Chem. Soc.

J. Org. Chem.

Heterocycl. Commun.