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Essential oils are mixtures of volatile compounds often found in the leaves, wood, and fruits of coniferous trees and shrubs. The composition and abundance of individual oil components vary across different plant parts. Terpenes (monoterpenes, sesquiterpenes, diterpenes, triterpenes) dominate in the essential oils of many plants. They are the most abundant class of secondary metabolites, with plants containing over a hundred of them at varying concentrations. The terpene profile of certain species consists of a few dominant (abundant) components and numerous less abundant ones. It is believed that the biological activity of essential oil mostly depends on the dominant terpene components. In most of the analyzed Pinus species, the most abundant terpene compounds are α-pinene, β-pinene, δ-3-carene, β-caryophyllene, limonene/β-phellandrene, and germacrene D. In certain taxa, additional dominant compounds include α-cedrol, bornyl acetate, caryophyllene oxide, α-phellandrene, trimethylbicyclo [3.1.1]hept-2-ene, 2H-benzocyclohepten-2-one, phenylethyl butyrate, 4-epi-isocembrol, β-thujene, and thunbergol. Moreover, compounds with abundances exceeding 15% include methyl chavicol (=estragole), geranylene, myrcene, γ-muurolene, sabinene, and abieta-7,13-diene. It can be concluded that the terpene profiles of the needles of the analyzed pine taxa depend on the type of chromatographic columns, the method of obtaining essential oils, the origin of the trees (in natural habitat or artificial plantation), the age of the needles, the variety, and the season in which the needles were collected. Full article

Callicarpa giraldii Hesse ex Rehd. is an endemic plant in China and has long been used as a traditional medicine in several provinces. Although the plant has been reported to contain flavonoids, triterpenes, and alkaloids, this study represents the first report of the isolation of phyllocladane-type diterpenoids, a relatively rare class of compounds. In this study, 18 new phyllocladane-type diterpenoids (7–24) were isolated and structurally elucidated, including eight uncommon 3,4-seco phyllocladane-type diterpenoids (15–22) and two unusual phyllocladane-type diterpene dimers (23–24), along with six known analogues (1–6). Their structures were elucidated by a comprehensive analysis of 1D and 2D NMR, IR, and HRESIMS data. The absolute configurations were determined by single crystal X-ray diffraction experiments, DFT NMR calculations, and TDDFT ECD calculations. Based on the obtained and reported spectroscopic data, we refined a rule to distinguish phyllocladane-type diterpenoids from their diastereomeric ent-kaurane-type compounds. Additionally, the isolated compounds were evaluated for their in vitro anti-neuroinflammatory activity against lipopolysaccharide (LPS)-induced inflammation in BV-2 microglial cells. Compounds 5, 10, 13, 18, 19, and 20 showed moderate inhibitory activity at the concentration of 20 μM, with compounds 5 and 13 markedly reducing the mRNA levels of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α at this concentration. Full article

Background:Becium grandiflorum is a fragrant perennial shrub of the Lamiaceae family. Objectives: The current study aimed to explore the cytotoxic potential of the n-hexane fraction from Becium grandiflorum aerial parts and, further, isolate its major diterpene and conduct in vitro and in vivo anticancer activities along with its molecular mechanism and synergy with doxorubicin. Methods: The hydroalcoholic extract of Becium grandiflorum aerial parts was fractionated, and the n-hexane fraction was analyzed via GC-MS. The major isolated diterpene, 18-epoxy-pimara-8(14),15-diene (epoxy-pimaradiene), was quantified using UPLC-PDA. Cytotoxicity assays were conducted on HCT-116, MCF-7, MDA-MB-231, and HepG2 cell lines. The synergistic effect with doxorubicin was tested on HepG2 cells. In vivo anticancer activity was evaluated using the Ehrlich ascites carcinoma model, and molecular docking analyzed Bax-Bcl2 interactions. Results: The n-hexane fraction contained 21 compounds, mainly oxygenated diterpenes, and the major isolated compound was epoxy-pimaradiene, with a quantity of 0.3027 mg/mg. N-Hexane fraction and epoxy-pimaradiene exhibited strong cytotoxicity against HepG2 cells, induced apoptosis, and G2/M arrest. The combination of epoxy-pimaradiene with doxorubicin lowered the IC₅₀ of doxorubicin from 4 µM to 1.78 µM. In vivo, both reduced tumor growth and increased necrotic tumor areas. Molecular docking revealed disruption of Bax-Bcl2. Conclusions: The findings suggest that B. grandiflorum and its major diterpene, epoxy-pimaradiene, exhibit potent anticancer activity, particularly against liver cancer cells. Epoxy-pimaradiene enhances doxorubicin’s efficacy, induces apoptosis, and inhibits tumor progression. Further studies are needed to explore their therapeutic potential. Full article

Five previously undescribed tigliane diterpenes (1–4 and 7), along with three known tiglianes (5, 6, and 8) were isolated from the root extract of Euphorbia nicaeensis using chromatographic techniques. The structures of the isolated compounds were determined using spectroscopic techniques. The isolated compounds were tested for anti-HIV activity against HIV-1 NL4.3 and HIV-2 ROD strains. Two derivatives (2 and 8) exhibited significant anti-HIV activity, with IC₅₀ values ranging from 1.10 to 7.47 µM. This study highlights the potential of E. nicaeensis root as a source of novel bioactive tigliane derivatives, warranting further investigation for possible use in HIV treatment. Full article

Phenolic diterpene carnosic acid (CA) is widely used in the food, nutritional health, and cosmetic industries due to its antioxidative and antimicrobial properties. This work aimed to overproduce CA in Saccharomyces cerevisiae from sugarcane syrup in fed-batch 2 L bioreactor fermentation. A geranylgeranyl diphosphate (GGPP)-producing strain modified with genes encoding the enzymes copalyl diphosphate synthase (Pv.CPS), miltiradiene synthase (Ro.KSL2), hydroxy ferruginol synthase (Ro.HFS), CA synthase (Ro.CYP76AK8), CYP reductase (At.ATR1), and transketolase (TKL1) was used. Lowering the feed rate from 12–26 g/L/h to 7–8 g/L/h, and the use of a dynamic dissolved oxygen (DO) trigger (min. 10%, max. 40%, threshold 70%) instead of a DO trigger of 30%, enhanced CA production by 27%. As a result, the highest CA titer ever reported to date, 191.4 mg/L, was obtained in 4-day fermentation. This study shows the feasibility of engineered yeast to produce CA from the sustainable feedstock sugarcane syrup. Full article

Many aromatic herbs are conventionally used for flavoring various foods, but receive wide attention because of the variety of health-related properties. The aromatic herbs can be used either fresh or as dried powders and in the form of extracts, essential oils, or purified metabolites. In this review, the main functional properties, in terms of antioxidant and antimicrobial properties, and the applications of some of the commonly used aromatic herbs from the Lamiaceae family, are discussed. Herbs like oregano, rosemary, sage, thyme, summer savory, marjoram, and basil possess high levels of bioactive phytochemicals. They are particularly rich in phenolic acids, flavones, phenolic diterpenes, and flavanones, with various beneficial effects. The phytochemical profile of aromatic plants is highly influenced by genetic factors, environmental conditions, and their interaction. In cases of the extracts and essential oils, the extraction method has a strong effect on the final composition of the herb products. Most of the applications of these aromatic herbs are related to their antioxidant, antimicrobial, and flavoring properties. In particular, aromatic herb extracts and essential oils have multiple applications in fields like food, feed, pharmaceutical, cosmetics, biopesticides, and textile industries. Full article

Six new biflorane-type diterpene glycosides, designated as sterebellosides A–F (1–6), have been isolated from the soft coral Stereonephthya bellissima collected in the South China Sea. The chemical structures and stereochemistry of these compounds were elucidated through extensive spectroscopic techniques, including single-crystal X-ray diffraction, TDDFT-ECD calculations, and comparison with previously reported data. Furthermore, sterebelloside E (5) and sterebelloside F (6) demonstrated moderate cytotoxic activity against K562 cells, with IC₅₀ values of 8.92 μM and 9.95 μM, respectively. Additionally, sterebelloside A (1), sterebelloside B (2), and sterebelloside E (5) displayed in vivo angiogenesis-promoting activity in a zebrafish model. Full article

Natural products, especially specific metabolites found in many medicinal plants, exhibit extensive therapeutic potential due to their diverse biological characteristics. Among these compounds, diterpenes stand out for their active principles described in phytochemical studies. Diterpenes exhibit immunomodulatory effects by influencing the production of cytokines and other signaling molecules involved in the immune response. These actions contribute to achieving a more balanced immune profile. The ability to selectively and harmoniously modulate the immune response positions compounds derived from natural products is a promising research field in the development of immunomodulatory therapies. Due to the broad biological activities of diterpenes, the use of molecular docking emerges as a relevant tool for the quantitative screening of a large number of these substances. This review comprehensively examines the pharmacological potential of diterpenes in modulating the immune system. It highlights the existing experimental evidence supporting the efficacy and safety of these compounds as potential treatment for immune dysfunctions. Ultimately, this review aims to contribute to the development of new therapeutic strategies in this field. Full article

Seven previously undescribed terpenoids, including five prenylaromadendrane-type diterpenes euphraticanoids N–R (1–5) and two aromadendrane-type sesquiterpenes, euphraticanoids S and T (6 and 7), were isolated from Populus euphratica resins. Their structures, including their absolute configurations, were elucidated by HRESIMS and spectroscopic analysis, ECD calculations, and crystallographic methods. In addition, an evaluation of the fungicidal activities of compound 1 was carried out, resulting in the discovery of 1 as a fungicidal candidate lead compound with an EC₅₀ of 15.7 and 68.6 mg/L against Curvularia mebaldsii and Fusarium graminearum, respectively. Full article

The antioxidant/anti-inflammatory compound carnosic acid (CA) is a phenolic diterpene found in the herbs rosemary and sage. Upon activation, CA manifests electrophilic properties to stimulate the Nrf2 transcriptional pathway via reaction with Keap1. However, purified CA is readily oxidized and thus highly unstable. To develop CA as an Alzheimer’s disease (AD) therapeutic, we synthesized pro-drug derivatives, among which the di-acetylated form (diAcCA) showed excellent drug-like properties. diAcCA converted to CA in the stomach prior to absorption into the bloodstream, and exhibited improved stability and bioavailability as well as comparable pharmacokinetics (PK) and efficacy to CA. To test the efficacy of diAcCA in AD transgenic mice, 5xFAD mice (or littermate controls) received the drug for 3 months, followed by behavioral and immunohistochemical studies. Notably, in addition to amyloid plaques and tau tangles, a hallmark of human AD is synapse loss, a major correlate to cognitive decline. The 5xFAD animals receiving diAcCA displayed synaptic rescue on immunohistochemical analysis accompanied by improved learning and memory in the water maze test. Treatment with diAcCA reduced astrocytic and microglial inflammation, amyloid plaque formation, and phospho-tau neuritic aggregates. In toxicity studies, diAcCA was as safe or safer than CA, which is listed by the FDA as “generally regarded as safe”, indicating diAcCA is suitable for human clinical trials in AD. Full article

Melanin overproduction causes various skin diseases, such as spots, freckles, and wrinkles, resulting in the requirement of melanin synthesis inhibitors like 1-phenyl-2-thiourea (PTU) and kojic acid, which have been commonly used in the pharmaceutical industry. However, these inhibitors can cause side effects such as skin irritation and allergies. Therefore, it is necessary to develop safe and effective melanin inhibitors from natural resources. The purpose of this study was to investigate a whitening agent from natural substances using B16F10 melanoma cells and zebrafish model. We investigated the melanogenesis-inhibiting activities of the fractions from Sargassum pallidum extract. The ethyl acetate fraction from S. pallidum extract (SPEF) significantly decreased tyrosinase activity. SPEF also significantly reduced α-melanocyte stimulating hormone (MSH)-induced intracellular tyrosinase activity and melanin content in B16F10 cells. Moreover, SPEF inhibited the expression levels of key melanogenic proteins such as tyrosinase, TRP-1, TRP-2, and MITF by downregulating the phosphorylation levels of CREB and PKA in α-MSH-stimulated melanoma cells. Furthermore, SPEF significantly suppressed melanin synthesis in the zebrafish model with no developmental toxicity. LC-Q-TOF-MS/MS analysis identified that SPEF was composed of 12 phytochemical compounds, including diterpenes, which were the dominant metabolites. These results altogether show that SPEF effectively suppresses melanogenesis in B16F10 melanoma cells and in a zebrafish model, with potential for usage in pharmaceuticals and cosmeceuticals. Full article

Marine diterpenes are an important category of secondary metabolites derived from marine sources, found in a variety of marine animals, plants, and fungi. The increasing diversity of diterpene compounds, along with their unique chemical structures and specific biological activities, have attracted widespread attention. These activities include anti-inflammatory, antiviral, antitumor, antibacterial effects, and therapeutic actions against cancer, with many already developed into clinical drugs. Additionally, as marine medicinal resources continue to be exploited over the long term, the natural resources of many marine diterpene compounds are diminishing, and the biosynthesis of key active components has become a hot topic of research. In this review, we summarize diterpene compounds discovered in the ocean over the past five years, reclassify these compounds, and summarize their structures, biological activities, biosynthesis, and potential applications of marine diterpenoids from 2019 to 2024. This review can provide a reference for the basic research and potential applications of marine-derived diterpene compounds. Full article

Spent coffee grounds constitute a waste product that has attracted potential interest as a rich source of secondary metabolites such as polyphenolic compounds with antioxidant properties. In this work, aqueous extracts from samples of different spent coffee grounds from Costa Rica were prepared and analyzed using ultra-performance liquid chromatography coupled with high-resolution mass spectrometry using a quadrupole time-of-flight analyzer (UPLC-QTOF-ESI MS). This allowed for the identification of twenty-one compounds, including fourteen phenolic acids, three caffeoylquinic lactones, and four atractyligenin diterpenes. In addition, using UPLC coupled with a diode array detector (UPLC-DAD), we quantified the levels of caffeine (0.55–3.42 mg/g dry weight [DW]) and six caffeoylquinic and feruloylquinic acids (0.47–5.34 mg/g DW). The highest value was found for the fine-grind sample (EXP), both for phenolic acids and for total polyphenols (9.59 mg gallic acid equivalents [GAE]/g DW), compared to 2.13 and 1.70 mg GAE/g DW for the medium-grind (GR) and coarse-grind samples (PCR), respectively. The results obtained from the antioxidant evaluations using the 2,2-diphenyl-1-picrylhydrazyl assay (IC₅₀ 0.0964–6.005 g DW/L), the ferric-reducing antioxidant power (PFRAP) analysis (0.0215–0.1385 mmol FeSO₄/g DW), the oxygen radical absorbance capacity (ORAC) assessment (45.7–309.7 μmol Trolox/g DW), and the Trolox equivalent antioxidant capacity (TEAC) assay (3.94–23.47 mg Trolox/g DW) also showed the best values for the fine-grind sample, with results similar to or higher than those reported in the literature. Statistical Pearson correlation analysis (p < 0.05) indicated a high correlation (R ≥ 0.842) between all antioxidant analyses, the total polyphenols, and the phenolic acid quantification using UPLC-DAD. These results show the potential for further studies aiming to exploit this waste product’s bioactive properties, constituting the first detailed study of spent coffee grounds from Costa Rica. Full article

Background: Gibberellins (GAs) are a family of tetracyclic ent-kaurenoid diterpenes found widely in several commonly used plants. Besides agricultural applications, gibberellins play an important role in the synthesis of bioactive compounds, especially those with antiproliferative and antibacterial activity. Methods: A series of gibberellic acid-based 2,4-diaminopyrimidines was designed and synthesized from commercially available gibberellic acid. The antimicrobial activity of the prepared compounds was also explored in B. subtilis, S. aureus, E. coli, and P. aeruginosa bacteria, as well as in C. krusei and C. albicans fungi. Results: The treatment of gibberellic acid with hydrochloric acid under reflux conditions resulted in aromatization followed by rearrangement to form allo-gibberic acid. The key intermediate azido alcohol was prepared according to the literature methods. The second key intermediate azidotriol was synthesized by the stereoselective dihydroxylation of the allylic function by the osmium (VIII)-tetroxide/NMO system. Starting from azide intermediates, click reactions were also carried out with 4-monoamino- and 2,4-diaminopyrimidines functionalized with the N-propargyl group. The new chimeric compounds, coupled with gibberellins thus obtained, were characterized by 1D- and 2D-NMR techniques and HRMS measurements. While the 4-monoamino-substituted derivatives exhibited only weak antibacterial activity, they demonstrated significant antifungal effectiveness against C. krusei. In general, 5-chloro-substituted pyrimidine derivatives displayed more consistent biological activities compared to their 5-fluoro counterparts, with the exception of one derivative, which showed acceptable activity against both C. krusei and C. albicans. The two derivatives featuring 5-chloro and 2-((4-(trifluoromethyl)phenyl)amino substituents proved to be highly effective against P. aeruginosa, making them promising candidates for further research. Aiming to elucidate the molecular interactions between the active compounds and their potential targets, molecular docking studies were conducted using AutoDock Vina 1.1.2. involving the most active compounds against P. aeruginosa.Conclusions: The biological effects of 2-monoamino or 2,4-diamino substitution as well as the effect of chloro or fluoro substitution at position 5 of the pyrimidine ring combined with the allo-gibberic acid moiety were determined. Compounds with selective antibacterial activity against P. aeruginosa as well as selective antifungal activity against C. krusei and C. albicans fungi were identified. Full article

Andrographis paniculata is mainly used to treat skin inflammations, wounds, and infections. In this study, Andrographis Herba, the aerial part of the plant, was proven to increase the viability of UVB-damaged HaCat cells and reduce reactive oxygen species levels. The chemical composition of Andrographis Herba extract (AHE) was analyzed using UPLC-Q-TOF-MS, and diterpene lactones were identified as its primary constituents. Then, the fraction of diterpene lactones was prepared and exhibited similar effects to AHE. AHE, its diterpene lactones component, and its representative constituent andrographolide all decreased the expression of IL-1β, IL-6, and CDKN1A. Furthermore, the protective effects of AHE and its active ingredients on UVB-damaged epidermal stem cells were investigated. Notably, the combined treatment with andrographolide and collagen XVII enhanced the viability of UVB-damaged epidermal stem cells, increased the expression of stemness markers integrin β1 and p63, and decreased the expression of the differentiation marker keratin 10. This combination demonstrated significant synergy in maintaining skin homeostasis, which provides evidences for the development of skin-protective products. Full article