Cembranoid Diterpenes Research Articles

Inhibition of Soluble Epoxide Hydrolase by Cembranoid Diterpenes from Soft Coral Sinularia maxima: Enzyme Kinetics, Molecular Docking, and Molecular Dynamics.

Soluble epoxide hydrolase (sEH) is essential for converting epoxy fatty acids, such as epoxyeicosatrienoic acids (EETs), into their dihydroxy forms. EETs play a crucial role in regulating blood pressure, mediating anti-inflammatory responses, and modulating pain, making sEH a key target for therapeutic interventions. Current research is increasingly focused on identifying sEH inhibitors from natural sources, particularly marine environments, which are rich in bioactive compounds due to their unique metabolic adaptations. In this study, the sEH inhibitory activities of ten cembranoid diterpenes (1-10) isolated from the soft coral Sinularia maxima were evaluated. Among them, compounds 3 and 9 exhibited considerable sEH inhibition, with IC50 values of 70.68 μM and 78.83 μM, respectively. Enzyme kinetics analysis revealed that these two active compounds inhibit sEH through a non-competitive mode. Additionally, in silico approaches, including molecular docking and molecular dynamics simulations, confirmed their stability and interactions with sEH, highlighting their potential as natural therapeutic agents for managing cardiovascular and inflammatory diseases.

Phytochemicals derived from Nicotiana tabacum L. plant contribute to pharmaceutical development.

The Nicotiana tabacum L. plant, a medicinal resource, holds significant potential for benefiting human health, as evidenced by its use in Native American and ancient Chinese cultures. Modern medical and pharmaceutical studies have investigated that the abundant and distinctive function metabolites in tobacco including nicotine, solanesol, cembranoid diterpenes, essential oil, seed oil and other tobacco extracts, avoiding the toxic components of smoke, mainly have the anti-oxidation, anti-lipid production, pro-lipid oxidation, pro-insulin sensitivity, anti-inflammation, anti-apoptosis and antimicrobial activities. They showed potential pharmaceutical value mainly as supplements or substitutes for treating neurodegenerative diseases including Alzheimer's and Parkinson's disease, inflammatory diseases including colitis, arthritis, sepsis, multiple sclerosis, and myocarditis, and metabolic syndrome including Obesity and fatty liver. This review comprehensively presents the research status and the molecular mechanisms of tobacco and its metabolites basing on almost all the English and Chinese literature in recent 20 years in the field of medicine and pharmacology. This review serves as a foundation for future research on the medicinal potential of tobacco plants.

Isopropyl (ene)-type Cembrane Diterpene an Important Chemotaxonomical Marker in Bornean Soft Coral Genus Sarcophyton

Two cembrane diterpenoids; (+)-11,12-epoxysarcophytol A (1) and sarcophytol W (2) were isolated from Sarcophyton sp. collected from Mantanani Island, Sabah. Secondary metabolites structures were elucidated based on spectroscopic data. This is the first record of cembranoid diterpenes isolated from the Bornean soft coral genus Sarcophyton. The isopropyl(ene)-type cembrane derivatives could be suggested as chemotaxonomical markers for soft coral genus Sarcophyton.

One new cembranoid diterpene from gum resin of Boswellia carterii

This study aims to study the chemical components from the gum resin of Boswellia carterii. Five cembranoid diterpenes were isolated from the gum resin of B. carterii by various of column chromatographies including silica gel, Sephadex LH-20, and semi-preparative HPLC. Their structures were identified on the basis of physicochemical properties, mass spectrometry(MS), nuclear magnetic resonance(NMR), Ultraviolet(UV) and infrared(IR) spectroscopic data. These compounds were identified as(1S,2E,4R,5S,7E,11E)-4-methoxy-5-hydroxycembrane(1),(1R~*,4R~*,5E,8E,12E,15E)-4-hydroxycembra-5,8,12,15-tetraene(2), cembrene A(3),(3S,4S,7R)-4-hydroxycembrane(4), and pavidolide D(5). Compound 1 was a new compound. Compounds 2, 4, and 5 were obtained from the gum resin of B. carterii for the first time. Compound 2 showed weak inhibition on the human liver cancer cell line HepG2.

Cryptic Species Account for the Seemingly Idiosyncratic Secondary Metabolism of Sarcophyton glaucum Specimens Collected in Palau.

Sarcophyton glaucum is one of the most abundant and chemically studied soft corals with over 100 natural products reported in the literature, primarily cembrane diterpenoids. Yet, wide variation in the chemistry observed from S. glaucum over the past 50 years has led to its reputation as a capricious producer of bioactive metabolites. Recent molecular phylogenetic analysis revealed that S. glaucum is not a single species but a complex of at least seven genetically distinct species not distinguishable using traditional taxonomic criteria. We hypothesized that perceived intraspecific chemical variation observed in S. glaucum was actually due to differences between cryptic species (interspecific variation). To test this hypothesis, we collected Sarcophyton samples in Palau, performed molecular phylogenetic analysis, and prepared chemical profiles of sample extracts using gas chromatography-flame ionization detection. Both unsupervised (principal component analysis) and supervised (linear discriminant analysis) statistical analyses of these profiles revealed a strong relationship between cryptic species membership and chemical profiles. Liquid chromatography with tandem mass spectrometry-based analysis using feature-based molecular networking permitted identification of the chemical drivers of this difference between clades, including cembranoid diterpenes (2R,11R,12R)-isosarcophytoxide (5), (2S,11R,12R)-isosarcophytoxide (6), and isosarcophine (7). Our results suggest that early chemical studies of Sarcophyton may have unknowingly conflated different cryptic species of S. glaucum, leading to apparently idiosyncratic chemical variation.

A Brief Review on New Naturally Occurring Cembranoid Diterpene Derivatives from the Soft Corals of the Genera Sarcophyton, Sinularia, and Lobophytum Since 2016.

This work reviews the new isolated cembranoid derivatives from species of the genera Sarcophyton, Sinularia, and Lobophytum as well as their biological properties, during 2016–2018. The compilation permitted to conclude that much more new cembranoid diterpenes were found in the soft corals of the genus Sarcophyton than in those belonging to the genera Lobophytum or Sinularia. Beyond the chemical composition, the biological properties were also reviewed, namely anti-microbial against several Gram-positive and Gram-negative bacteria and fungi, anti-inflammatory and anti-tumoral against several types of cancer cells. In spite of the biological activities detected in almost all samples, there is a remarkable diversity in the results which may be attributed to the chemical variability that needs to be deepened in order to develop new molecules with potential application in medicine.

A Review on Bioactivities of Tobacco Cembranoid Diterpenes.

Cembranoids are carbocyclic diterpenes comprising four isoprene units and are natural products with a parent skeleton consisting of a 14-membered ring. They have gained wide interest in recent years and are a major hotspot in the research of natural product chemistry. Since 1962, various tobacco cembranoid diterpenes have been identified. This review systematically discusses and summarises the excellent antimicrobial, insecticidal, cytotoxic and neuroprotective activities of tobacco cembranoid diterpenes. These compounds show potential to be developed as botanical fungicides, cytotoxic drugs and drugs for the treatment of human immunodeficiency virus, Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative diseases. However, there are relatively few studies on the structure–activity relationship (SAR) of tobacco cembranoid diterpenes. Therefore, future studies should focus on their structural modification, SAR and biogenic relationships.

Crystal structure and configuration revision of 9-hydroxy-7,8-dehydro-sarcotrocheliol and sarcotrocheliol

Herein, we report the isolation and stereo-structure of rare pyrane-based cembranoid diterpenes, 9-hydroxy-7,8-dehydro-sarcotrocheliol (1) and sarcotrocheliol (2), from Sarcophyton trocheliophorum collected from Red Sea. Absolute configurations of both compounds were revised based on single crystal X-ray analyses.

Quorum Sensing Interference and Structural Variation of Quorum Sensing Mimics in Australian Soft Coral

Bacterial Quorum Sensing (QS), the indirect regulation of gene expression through production and detection of small diffusible molecules, has emerged as a point of interaction between eukaryotic host organisms and their associated microbial communities. The extracellular nature of QS molecules enables interference in QS systems, in many cases via mimicry. This study targeted QS induction and inhibition in soft coral holobionts, as many soft coral species commonly contain compounds with structural similarities to the well-studied bacterial QS molecules acyl homoserine lactones. Screening with two bacterial biosensors, Agrobacterium tumefaciens A136 and Chromobacterium violaceum CV026, demonstrated that QS interference differed between the two biosensor strains and extended across the soft coral families Alcyoniidae, Clavulariidae, Nephtheidae, and Xeniidae. Bioassay-guided fractionation revealed chemical activity patterns, particularly in the induction of QS. Cembranoid diterpenes from active fractions were purified and tested for QS interference activity. Interestingly, the type of QS activity (induction or inhibition) in A. tumefaciens A136 correlated with structural variability of the secondary oxygen ring; cembranoid diterpeneswith a furan ring or five-membered lactone induced QS, while compounds with larger (six or seven membered) lactone rings inhibited QS. Addition of the dominant cembranoid diterpene in the soft coral Lobophytum compactum, isolobophytolide, to bacterial culture media increased the number and morphological diversity of bacteria recovered from the mucosal layer of this soft coral, demonstrating a selective effect on certain members of the soft coral bacterial community. The identity and QS activity of recovered isolates differed between the mucosal layers of L. compactum and Sinularia flexibilis. In conclusion, this study provides information on the complexity of the interaction between soft corals and their associated bacteria, as well as, a structural understanding of how QS mimic compounds are able to interfere with a bacterial communication system.

New pyranosyl cembranoid diterpenes from Sarcophyton trocheliophorum

During our continual searching programme for novel bioactive metabolites from Sarcophyton trocheliophorum, collected from Red Sea, we describe herein the isolation and structural elucidation of further two new pyrane-based cembranoid diterpenes: 9-hydroxy-7,8-dehydro-sarcotrocheliol (1) and 8,9-expoy-sarcotrocheliol acetate (2), along with the well-known sarcotrocheliol acetate (3), (+)-sarcophine (4), (+)-sarcophytoxide (5) and (-)-sarcophytoxide (6). The chemical structures of compounds 1 and 2 were determined on the basis of 1D and 2D NMR (1H, 13C, 1H–1H COSY, HMQC, HMBC and NOE), mass spectra (ESI and HR-ESIMS) and by comparison with related structures. The antimicrobial activities of the reported compounds 1–6 were investigated. According to the molecular docking study of compounds 1–6 using 3D structure of α,β tubulin in complex with taxol (PDB code 1JFF) and epothilone A (PDB code 1TVK), sarcophine (4) displayed the highest affinity towards both crystal structures, followed by 5 and 6, meanwhile pyrane-based cembranoid diterpenes (1–3) showed less affinity.

Cytotoxic Activity of Two Cembranoid Diterpenes from Nicotiana Sylvestris Against Three Human Cancer Cell Lines

Background: Two cembranoid diterpenes, [(1S, 2E, 4R, 6R, 7E, 11E)-2, 7, 11-cembratriene-4, 6-diol] (1) and its epimer [(1S, 2E, 4S, 6R,7E,11E)-2, 7, 11-cembratriene-4, 6-diol] (2) were isolated from surface dichloromethane washings and chloroform extract of Nicotiana sylvestris leaves. Methods: The compounds were purified using silica gel column- thin layer- and flash column chromatography methods. The structures of the isolated compounds were elucidated using spectroscopic analysis and their 1H and 13C NMR spectroscopic data were compared with those of authentic samples reported in the literature. The cytotoxic activity of 1 and 2 against three human cancer cell lines, including LS180 (human colon adenocarcinoma), MCF-7 (human breast adenocarcinoma) and MOLT-4 (human lymphoblastic leukemia) were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric bioassay. Results: The IC50 values of compounds 1 and 2 were calculated to be between (28.4±3.7 up to 44.0±6.4 µM) (mean±S.E.M.) for the above mentioned cell lines.

Cytotoxic Activity of Two Cembranoid Diterpenes from Against Three Human Cancer Cell Lines

Cytotoxic Activity of Two Cembranoid Diterpenes from Against Three Human Cancer Cell Lines

Cytotoxic Effects of Sarcophyton sp. Soft Corals-Is There a Correlation to Their NMR Fingerprints?

Sarcophyton sp. soft corals are rich in cembranoid diterpenes, which represent the main chemical defense of corals against their natural predators in addition to their myriad biological effects in humans. Quantitative NMR (qNMR) was applied for assessing the diterpene variation in 16 soft coral specimens in the context of their genotype, origin, and growing habitat. qNMR revealed high diterpene levels in Sarcophyton sp. compared to Sinularia and Lobophyton, with (ent)sarcophines as major components (17–100 µg/mg) of the coral tissues. Multivariate data analysis was employed to classify samples based on the quantified level of diterpenes, and compared to the untargeted NMR approach. Results revealed that qNMR provided a stronger classification model of Sarcophyton sp. than untargeted NMR fingerprinting. Additionally, cytotoxicity of soft coral crude extracts was assessed against androgen-dependent prostate cancer cell lines (PC3) and androgen-independent colon cancer cell lines (HT-29), with IC50 values ranging from 10–60 µg/mL. No obvious correlation between the extracts’ IC50 values and their diterpene levels was found using either Spearman or Pearson correlations. This suggests that this type of bioactivity may not be easily predicted by NMR metabolomics in soft corals, or is not strongly correlated to measured diterpene levels.

Secondary metabolome and its defensive role in the aeolidoidean Phyllodesmium longicirrum, (Gastropoda, Heterobranchia, Nudibranchia).

Phyllodesmium longicirrum is the largest aeolidoidean species known to date, and extremely rich in terpenoid chemistry. Herein we report the isolation of a total of 19 secondary metabolites from a single specimen of this species, i.e., steroids 1–4, cembranoid diterpenes 5–13, complex biscembranoids 14 and 15, and the chatancin-type diterpenes 16–19. These compounds resemble those from soft corals of the genus Sarcophyton, of which to date, however, only S. trocheliophorum is described as a food source for P. longicirrum. Fish feeding deterrent activity was determined using the tropical puffer fish Canthigaster solandri, and showed activity for (2S)-isosarcophytoxide (10), cembranoid bisepoxide 12 and 4-oxochatancin (16). Determining the metabolome of P. longicirrum and its bioactivity, makes it evident that this seemingly vulnerable soft bodied animal is well protected from fish by its chemical arsenal.

Antibacterial and cytotoxic properties of isoprenoids from the red sea soft coral, <i>Lobophytum</i> sp

Purpose: To evaluate the antibacterial and cytotoxic activities of the secondary metabolites of Lobophytum sp. Methods: Maceration with methanol: chloroform (1: 1) was applied to extract the coral material. Chromatographic and spectroscopic techniques were employed for fractionation, isolation and elucidation of pure compounds. Antibacterial activities were performed by well diffusion method against three Gram-positive and four Gram-negative bacteria. Brine shrimp lethality test was employed to predict toxicity, while antitumor activity were tested by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) method against Ehrlich carcinoma cells. Results: Four sesquiterpenes, one cembranoid type diterpenes and two steroids were isolated. 1 exhibited significant antibacterial activity against four tested bacteria (P. aeruginosa, S. aureus, S. epidermis, and S. pneumonia) with MIC value of 15 mu g/mL. Moreover, 1 showed high diameter zone of inhibition ranging from 16 - 18 mm against test bacteria. Compounds 4 and 5 displayed moderate antibacterial activity against all test bacteria with inhibition zone diameter (IZD) ranging from 11 - 15 mm and MIC values of 30 mu g/mL. 2, 3, 6 and 7 exhibited weak antibacterial activity (IZD, 7 - 11 mm; MIC = 30 mu g/mL). In addition, only diterpene compound (4) showed high toxicity against A. Salina and antitumor activity against Erhlich carcinoma cells with the LD50 of 25 and 50 mu g/mL, respectively. Conclusion: This study reveals the strong antibacterial activity of sesquiterpene alismol (1) and the potential antibacterial and antitumor activity of cembranoid type diterpene, cembrene A (4).

Three new cembranoids from the Bornean soft coral Nephthea sp.

Three new cembranoid diterpenes, 10-hydroxy-nephthenol acetate (1), 7,8-epoxy-10-hydroxy-nephthenol acetate (2), and 6-acetoxy-7,8-epoxy-10-hydroxy-nephthenol acetate (3), along with a known compound, 6-acetoxy-7,8-epoxy-nephthenol acetate (4), were isolated from the Bornean soft coral Nephthea sp. Antibacterial and anticancer activities were exhibited by compounds 1 and 2 against Staphylococcus aureus (ATCC 6538)/Escherichia coli (ATCC 13311) and Hela/MCF-7, respectively.

New antimicrobial biscembrane hydrocarbon and cembranoid diterpenes from the soft coral Sarcophyton trocheliophorum

A new tetracyclic biscembrane hydrocarbon, trocheliane (1), along with two new cembranoid diterpenes, sarcotrocheldiol A (2) and B (3), and the known diterpene cembrene-C (4), were isolated from the Red Sea soft coral Sarcophyton trocheliophorum. The structures and relative stereochemistry of the compounds were elucidated by interpretation of MS, 1 D NMR, and 2 D NMR experiments. The sensitivity of some pathogenic bacteria used as test organisms to the new compounds 1-3 was determined. 1 showed appreciable antimicrobial activity with the diameter of inhibition zones ranging from 11 to 18 mm. 1 was active against the two multidrug resistant bacteria Acinetobacter baumannii and Staphylococcus aureus. Minimal inhibitory concentrations (MICs) of compound 1 were recorded for all the tested bacteria using the fluorescein diacetate method and the recorded MIC values ranged from 4 to 6 $\mu $M.

Anti-Protozoal Activities of Cembrane-Type Diterpenes from Vietnamese Soft Corals.

Based on our previous finding that certain cembranoid diterpenes possess selective toxicity against protozoan pathogens of tropical diseases such as Trypanosoma and Plasmodium, we have subjected a series of 34 cembranes isolated from soft corals living in the Vietnamese sea to an in vitro screening for anti-protozoal activity against Trypanosoma brucei rhodesiense (Tbr), T. cruzi (Tc), Leishmania donovani (Ld), and Plasmodium falciparum (Pf). Twelve of the tested compounds displayed significant activity against at least one of the parasites. Specifically, 7S,8S-epoxy-1,3,11-cembratriene-16-oic methyl ester (1), (1R,4R,2E,7E,11E)-cembra-2,7,11-trien-4-ol (2), crassumol D (12), crassumol E (13), and (1S,2E,4S,6E,8S,11S)-2,6,12(20)-cembrantriene-4,8,11-triol (16) from Lobophytum crassum, L. laevigatum, and Sinularia maxima showed the highest level of inhibitory activity against T. b. rhodesiense, with IC50 values of about 1 µM or less. Lobocrasol A (6) and lobocrasol C (8) from L. crassum and L. laevigatum exhibited particularly significant inhibitory effects on L. donovani with IC50 values < 0.2 µM. The best antiplasmodial effect was exerted by laevigatol A (10), with an IC50 value of about 3.0 µM. The cytotoxicity of the active compounds on L6 rat skeletal myoblast cell was also assessed and found to be insignificant in all cases. This is the first report on anti-protozoal activity of these compounds, and points out the potential of the soft corals in discovery of new anti-protozoal lead compounds.

ChemInform Abstract: Cembranoid Diterpenes from the Soft Coral Lobophytum crassum and Their Antiinflammatory Activities

Abstractisolation, structure determination and antiinflammatory effects of nine cembranoid diterpenes including four new compounds, crassumols D—G (I)—(IV), respectively

2+2] Photocycloaddition Studies on Complex Tetronic Acid Esters Related to the Synthesis of Cembranoid Diterpenes

Twelve different tetronic acid esters bearing two potentially reactive olefinic groups were prepared and subjected to [2+2] photocycloaddition reactions by irradiation at λ = 254 nm in tert-butanol (5 mM). The diastereoselectivity and regioselectivity of the reaction was studied with regard to the synthesis of cembranoid diterpenes. When the tetronic acid core carried an alk-3-enyl substituent in the γ-position and an alk-3-enyloxy substituent in the β-position, the undesired γ-products prevailed and were formed in 48–81% yield. Altering the γ-alk-3-enyl substituent into an alk-3-ynyl or alk-2-ynyl substituent, resulted in formation of the desired β-photocycloaddition products. The latter products were obtained in yields of 56–88%, with two out of three products exhibiting very high regio- and diastereoselectivity.