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• Croton is a genus with over 1300 species that are endemic to the tropics and subtropics. • Diterpenoids make up 67.2 % of the compounds reported in this genus. • Based on predicted drug-likeness, 38 % of Croton compounds obey Lipinski's rule of five. • Croton compounds have comparable physicochemical properties to FDA-approved drugs. The genus Croton (Euphorbiaceae family) is constituted of approximately 1300 species with remarkable ethnomedicinal backgrounds supported by extensive pharmacological studies alongside over 900 compounds associated with some of the activities. However, there is no systematic review of the compounds' physicochemical features in tandem with their absorption, distribution, metabolism, extraction, and toxicity (ADMET) to corroborate both ethnomedicinal and pharmacological potential. This study focused on a virtual analysis of the physicochemical-ADMET properties of compounds from the genus Croton reported between 1990 and 2024. Various electronic databases, namely Google, Google Scholar, Scopus, ScienceDirect, Biomed Central, and Pubmed, were used to search for information related to the chemistry and pharmacology of Croton species. The physicochemical, ADMET and Scaffold information of the reported croton compounds were obtained from SWISSADME, pKCSM, and Data Warrior webservers, which were then analyzed by Origin Pro 2023 statistical software. Diterpenoids (67.2 %), alkaloids (11.1 %), sesquiterpenes (4.7 %), flavonoids (3.2 %), other terpenoids (Sesterterpenoid and triterpenoids; 2.7 %), monoterpenoids (1.7 %), megastigmane glycosides (2.2 %), proanthocyanidins (0.8 %), and other assorted compounds (6.4 %) make up the total of 900 compounds reported among the genus Croton between 1990 and 2024. Based on principal component analysis (PCA) results (PC1 and PC2, with total variances of 43.79 % and 16.50 %, respectively), most of these compounds have the same chemical space as FDA-approved medications. The biological activity that was most frequently reported was cytotoxicity (52 %) followed by anti-inflammatory actions (13 %). After the ADME screening, 38 % of the Croton compounds met the predetermined criteria for drug-likeness while toxicity analysis cleared 35.487 %, as nontoxic. The primary appropriate therapeutic candidates identified by the post- ADMET analysis were clerodanes, kauranes, labdanes and abietanes compounds, with respective ratios of 10, 10, 10, and 5 %. Alkaloids (5 %), crotofolanes at 20 %, and sesquiterpene majorly at 40 % were too determined to be appropriate therapeutic candidates. The majority of these compounds are drug-like with recommended ADME/Tox profiles. Given the promising cytotoxic potential of compounds from the genus Croton , further studies are warranted to determine their therapeutic applications and optimize their pharmaceutical development. [Display omitted] [ABSTRACT FROM AUTHOR]

In the present study, we have evaluated the cytotoxic activity of 282 extracts from 72 native plant species of the Brazilian Atlantic Forest biome. As a result, Casearia arborea and Sorocea hilarii leaves extracts showed cytotoxic activity against three tumour cell lines tested (B16F10, SW480 and Jurkat). After bioassay-guided fractionation, the bioactive fractions were submitted to the dereplication study via High-performance Liquid Chromatography, connected to High-resolution Mass Spectrometry (HPLC-ESI-QTOF/MS) analysis, combined with a Global Natural Products Social Molecular Networking (GNPS) tool. A combination of bioactivity-guided and dereplication approaches resulted in the putative annotation of 27 clerodane diterpenes and 9 flavonoids as main compounds present in the cytotoxic fractions of C. arborea. Regarding the active fraction of S. hilarii, 10 megastigmans, 17 spirostane steroids derivatives and 2 lignans were putatively identified. In conclusion, Casearia arborea and Sorocea hilarii are potential sources of antitumor compounds. [ABSTRACT FROM AUTHOR]

Safer analgesic drugs remain a hard challenge because of cardiovascular and/or gastrointestinal toxicity, mainly. So, this study evaluated in vivo the antiproliferative actions of a fraction with casearins (FC) from Casearia sylvestris leaves against human colorectal carcinomas and antihyperalgesic effects on inflammatory- or opiate-based pain relief and oncologic pain in Sarcoma 180 (S180)-bearing mice. Moreover, docking investigations evaluated the binding among Casearin X and NMDA(N-methyl-D-aspartate)-type glutamate receptors. HCT-116 colorectal carcinoma-xenografted mice were treated with FC for 15 days. Antinociceptive assays included chemically induced algesia and investigated mechanisms by pharmacological blockade. Intraplantar region S180-bearing animals received a single dose of FC and were examined for mechanical allodynia and behavior alterations. AutoDock Vina determined molecular interactions among Cas X and NMDA receptor subunits. FC reduced tumor growth at i.p. (5 and 10 mg/kg) and oral (25 mg/kg/day) doses (31.12–39.27%). FC reduced abdominal pain, as confirmed by formalin and glutamate protocols, whose antinociception activity was blocked by naloxone and L-NAME (neurogenic phase) and naloxone, atropine, and flumazenil (inflammatory phase). Meanwhile, glibenclamide potentiated the FC analgesic effects. FC increased the paw withdrawal threshold without producing changes in exploratory parameters or motor coordination. Cas X generated a more stable complex with active sites of the NMDA receptor GluN2B subunits. FC is a promising antitumor agent against colorectal carcinomas, has peripheral analgesic effects by desensitizing secondary afferent neurons, and inhibits glutamate release from presynaptic neurons and/or their action on cognate receptors. These findings emphasize the use of clerodane diterpenes against cancer-related pain conditions. [ABSTRACT FROM AUTHOR]

New substances with antimicrobial properties are needed to successfully treat emerging human, animal, or plant pathogens. Seven clerodane diterpenes, previously isolated from giant goldenrod (Solidago gigantea) root, were tested against Gram-positive Bacillus subtilis, Bacillus spizizenii and Rhodococcus fascians by measuring minimal bactericidal concentration (MBC), minimal inhibitory concentration (MIC) and half-maximal inhibitory concentration (IC50). Two of them, Sg3a (a dialdehyde) and Sg6 (solidagoic acid B), were proved to be the most effective and were selected for further study. Bacillus spizizenii was incubated with the two diterpenes for shorter (1 h) or longer (5 h) periods and then subjected to genome-wide transcriptional analyses. Only a limited number of common genes (28 genes) were differentially regulated after each treatment, and these were mainly related to the restoration of cell membrane integrity and to membrane-related transports. Changes in gene activity indicated that, among other things, K+ and Na+ homeostasis, pH and membrane electron transport processes may have been affected. Activated export systems can be involved in the removal of harmful molecules from the bacterial cells. Inhibition of bacterial chemotaxis and flagellar assembly, as well as activation of genes for the biosynthesis of secondary metabolites, were observed as a general response. Depending on the diterpenes and the duration of the treatments, down-regulation of the protein synthesis-related, oxidative phosphorylation, signal transduction and transcription factor genes was found. In other cases, up-regulation of the genes of oxidation–reduction processes, sporulation and cell wall modification could be detected. Comparison of the effect of diterpenes with the changes induced by different environmental and nutritional conditions revealed several overlapping processes with stress responses. For example, the Sg6 treatment seems to have caused a starvation-like condition. In summary, there were both common and diterpene-specific changes in the transcriptome, and these changes were also dependent on the length of treatments. The results also indicated that Sg6 exerted its effect more slowly than Sg3a, but ultimately its effect was greater. [ABSTRACT FROM AUTHOR]

SUMMARY: Scutellaria barbata is a traditional Chinese herb medicine and a major source of bioactive clerodane diterpenoids. However, barely clerodanes have been isolated from the closely related S. baicalensis. Here we assembled a chromosome‐level genome of S. barbata and identified three class II clerodane diterpene synthases (SbarKPS1, SbarKPS2 and SbaiKPS1) from these two organisms. Using in vitro and in vivo assays, SbarKPS1 was characterized as a monofunctional (−)‐kolavenyl diphosphate synthases ((−)‐KPS), while SbarKPS2 and SbaiKPS1 produced major neo‐cleroda‐4(18),13E‐dienyl diphosphate with small amount of (−)‐KPP. SbarKPS1 and SbarKPS2 shared a high protein sequence identity and formed a tandem gene pair, indicating tandem duplication and sub‐functionalization probably led to the evolution of monofunctional (−)‐KPS in S. barbata. Additionally, SbarKPS1 and SbarKPS2 were primarily expressed in the leaves and flowers of S. barbata, which was consistent with the distribution of major clerodane diterpenoids scutebarbatine A and B. In contrast, SbaiKPS1 was barely expressed in any tissue of S. baicalensis. We further explored the downstream class I diTPS by functional characterizing of SbarKSL3 and SbarKSL4. Unfortunately, no dephosphorylated product was detected in the coupled assays with SbarKSL3/KSL4 and four class II diTPSs (SbarKPS1, SbarKPS2, SbarCPS2 and SbarCPS4) when a phosphatase inhibitor cocktail was included. Co‐expression of SbarKSL3/KSL4 with class II diTPSs in yeast cells did not increase the yield of the corresponding dephosphorylated products, either. Together, these findings elucidated the involvement of two class II diTPSs in clerodane biosynthesis in S. barbata, while the class I diTPS is likely not responsible for the subsequent dephosphorylation step. Significance Statement: This study reveals that the class II clerodane diTPS is one of the key factors contributing to the distinct clerodane diterpenoid profiles between S. barbata and S. baicalensis; and strongly indicates that class I diTPS is not involved in the clerodane diterpenoid biosynthesis in S. barbata. [ABSTRACT FROM AUTHOR]

The secondary metabolites of clerodane diterpenoids have been found in several plant species from various families and in other organisms. In this review, we included articles on clerodanes and neo-clerodanes with cytotoxic or anti-inflammatory activity from 2015 to February 2023. A search was conducted in the following databases: PubMed, Google Scholar and Science Direct, using the keywords clerodanes or neo-clerodanes with cytotoxicity or anti-inflammatory activity. In this work, we present studies on these diterpenes with anti-inflammatory effects from 18 species belonging to 7 families and those with cytotoxic activity from 25 species belonging to 9 families. These plants are mostly from the Lamiaceae, Salicaceae, Menispermaceae and Euphorbiaceae families. In summary, clerodane diterpenes have activity against different cell cancer lines. Specific antiproliferative mechanisms related to the wide range of clerodanes known today have been described, since many of these compounds have been identified, some of which we barely know their properties. It is very possible that there are even more compounds than those described today, in such a way that makes it an open field to discover. Furthermore, some diterpenes presented in this review have already-known therapeutic targets, and therefore, their potential adverse effects can be predicted in some way. [ABSTRACT FROM AUTHOR]

This article, published in Chemistry of Natural Compounds, provides information on the volatile components of Casearia capitellata, a species of the Casearia genus found in Malaysia. The Casearia genus consists of approximately 180 species found in various regions around the world, and some of these plants have been used in traditional medicine for treating various ailments. Previous studies have identified terpenoids, including oxygenated diterpenoids, as the main compounds in Casearia species. The article specifically focuses on the chemical composition of the essential oil extracted from the leaves of Casearia capitellata, which mainly consists of sesquiterpenes hydrocarbons and oxygenated sesquiterpenes. The major components of the essential oil include β-caryophyllene, bicyclogermacrene, germacrene D, α-zingiberene, viridiflorol, and germacrene B. The essential oil also showed activity against two cancer cell lines. [Extracted from the article]

Endophytes have been shown to be a source of novel drug prototypes. The Casearia genus is known for presenting cytotoxic clerodane diterpenes; however, there are few reports on secondary metabolites produced by its fungal microbiota. Thus, in the present study endophytic fungi obtained from the fresh leaves of C. arborea were grown in potato dextrose broth and rice to perform a secondary metabolite prospection study. The cytotoxic profile of the crude extracts at 10 µg/mL was determined by a colorimetric assay on tumor cell lines. The endophytes producing cytotoxic extracts were identified through phylogenetic analysis and belong to Diaporthe and Colletotrichum species. Metabolites present in these extracts were organized in molecular networking format based on HRMS-MS, and a dereplication process was performed to target compounds for chromatographic purification. Metabolic classes, such as lipids, peptides, alkaloids, and polyketides were annotated, and octaketide and cytochalasin derivatives were investigated. Cytochalasin H was purified from the cytotoxic Diaporthe sp. CarGL8 extract and its cytotoxic activity was determined on human cancer cell lines A549, MCF-7, and HepG2. The data collected in the present study showed that molecular networking is useful to understand the chemical profile of complex matrices to target compounds, minimizing the cost and time spent in purification processes. [ABSTRACT FROM AUTHOR]

Extensive research over the past decades has identified numerous phytochemicals that could represent an important source of anti-cancer compounds. There is an immediate need for less toxic and more effective preventive and therapeutic strategies for the treatment of cancer. Natural compounds are considered suitable candidates for the development of new anti-cancer drugs due to their pleiotropic actions on target events with multiple manners. This comprehensive review highlighted the most relevant findings achieved in the screening of phytochemicals for anticancer drug development, particularly focused on a promising class of phytochemicals such as diterpenes with abietane, clerodane, and labdane skeleton. The chemical structure of these compounds, their main natural sources, and mechanisms of action were critically discussed. [ABSTRACT FROM AUTHOR]

Diterpenes are secondary metabolites that have attracted much attention due to their potential biological activities including anti-cancer potential. The aim of the current study is to assess the anticancer potential of the six known clerodane diterpenes (1–6) isolated from Polyalthia longifolia seeds and their underlying molecular mechanisms. These compounds were evaluated for their cytotoxicity in vitro by using MTT assays. The "two-phase model" with NDEA and PB ad libitum was used for induction of HCC and sorafenib was used as the standard drug. Prophylactic studies were carried out for compounds 4/6 at both low (5 mg/kg b.w) and high (10 mg/kg b.w) doses. Based on the MTT assay results, the two best compounds, 4 and 6, were selected for in vivo studies. The results showed that treatment with compound 4/6 significantly restored the changes in biochemical parameters and liver morphology observed in (NDEA + PB)-induced HCC rats. Additionally, the docking studies showed that compound 4/6 interacted with several key proteins such as MDM2, TNF-α, FAK, thereby inhibiting these proteins and reversing the negative impacts of NDEA. In conclusion, our results suggested that compounds 4 and 6 are potential therapeutic agents for HCC, mostly due to their ability to control typical cancer pathways. [ABSTRACT FROM AUTHOR]

A new clerodane diterpene, 2β-methoxyhardwickiic acid (1), and four known compounds (2–5) were isolated from the twigs of Monoon membranifolium. The structure of the new compound was determined by extensive spectroscopic methods and ESITOFMS data. The absolute configuration of 1 was established by a comparison of its ECD spectrum and specific rotation with those of related previously reported compounds. All compounds were evaluated for their nitric oxide (NO) production inhibitory activities in RAW264.7 macrophage cells. Compounds 3 and 5 inhibited NO production with IC50 values of 16.1 and 28.9 μM, respectively, which were better than that of standard compound, indomethacin (IC50 = 32.2 μM). [ABSTRACT FROM AUTHOR]

Salvia is the most diverse genus within the mint family (Lamiaceae), many of its species are well-known due to their medicinal and culinary uses. Most of the ethnopharmacological and phytochemical studies on Salvia are centred on species from the European and Asian clades. However, studies about the most diverse clade, the Neotropical sages (Salvia subgenus Calosphace ; 587 spp.), are relatively scarce. This review aims to compile the information on the traditional medicinal uses, pharmacological and phytochemistry properties of the Neotropical sages. To do so, we carried out a comprehensive review of the articles available in different online databases published from the past to 2022 (i.e., PubMed, Scopus, and Web of Science, among others) and summarized the information in tables. To uncover phylogenetic patterns in the distribution of four different groups of metabolites (mono-, sesqui-, di-, and triterpenes), we generated presence-absence matrices and plotted the tip states over a dated phylogeny of Salvia. We found several studies involving Mexican species of Salvia , but only a few about taxa from other diversity centres. The main traditional uses of the Mexican species of Calosphace are medicinal and ceremonial. In traditional medicine 56 species are used to treat diseases from 17 categories according to the WHO, plus cultural-bound syndromes. Pharmacological studies reveal a wide range of biological properties (e.g., antinociceptive, anti-inflammatory, anxiolytic, cytotoxic, and antidiabetic, etc.) found in extracts and isolated compounds of 38 Neotropical sages. From extracts of these species, at least 109 compounds have been isolated, identified and evaluated pharmacologically; 73 of these compounds are clerodanes, 21 abietanes, six flavonoids, five sesquiterpenoids, and four triterpenoids. The most characteristic metabolites found in the Neotropical sages are the diterpenes, particularly clerodanes (e.g., Amarisolide A, Tilifodiolide), that are found almost exclusively in this group. The Neotropical sages are a promising resource in the production of herbal medication, but studies that corroborate the properties that have been attributed to them in traditional medicine are scarce. Research of these metabolites guided by the phylogenies is recommended, since closely related species tend to share the presence of similar compounds and thus similar medicinal properties. [ABSTRACT FROM AUTHOR]

Nowadays, new leishmanicidal drugs are needed and natural products arise as a promising alternative source. Therefore, bioguided fractionation of a hydroethanolic extract from the stem bark of Croton echioides Baill. were conducted based on its antileishmanial activity. Two novel neo-clerodane diterpenoids methyl-15,16-epoxy-3,13(16),14-neo-clerodatrien-17,18-dicarboxylate (1) and dimethyl-3-oxo-15,16-epoxy-13(16),14-neo-clerodadien-17,18-dicarboxylate (2) were isolated, as well as four known compounds (3–6) and lupeol, from the hexane fraction. Their structures were established by NMR analysis. The crude extract, fractions and the compounds (1 and 3–6) were evaluated for their in vitro antileishmanial activity and cytotoxicity against macrophages J774A.1. The selectivity index (SI) were calculated. The most active compound against promastigote forms of L. amazonensis was the clerodane diterpene 4, with IC50 values of 8.3 µM and SI value of 80.9. Our results highlighted stem bark of Croton echioides Baill. as a promising source for the development of a new chemotherapeutic agent to combat leishmaniasis. [ABSTRACT FROM AUTHOR]

Phytochemical studies of methylene chloride soluble fraction from the 70% aqueous-alcoholic extract of Polyalthia longifolia (leaves) resulted in the isolation of two known clerodane diterpenes, namely: 16α-hydroxycleroda-3,13(14)-dien-16,15-olide (1) and (4→2)-abeo-16-hydroxy-cleroda-2,13(14)-dien-15,16-olide-3-al (2). The isolated compounds were evaluated for their anti-histaminic and anti-Helicobacter pylori activities. Compound 1 was more potent than 2 with IC50 29.7 μg/mL and 189.2 μg/mL in the anti-histaminic assay and MIC equals to 31.25 μg/mL and 125 μg/mL in the anti-H. pylori assay, as compared with diclofenac (IC50 = 17.9 μg/mL) and clarithromycin (MIC = 1.95 μg/mL), respectively. The differences in their structures, as well as their activity results, indicated important characteristic features necessary for activity. It was suggested that the decalin moiety in 1 was important for both activities. On the other hand, the (4→2)-abeo migration in 2 reduced both activities. The potent activities of 1 suggest its potential application as an anti-histaminic and antimicrobial agent. [ABSTRACT FROM AUTHOR]

Chromatographic separation of crude extracts from the leaves and stems of Croton poomae Esser led to the isolation of two new clerodane diterpenes crotonolide K (1) and furocrotinsulolide A acetate (2) and six known clerodane diterpenes (3–8), together with twelve known compounds (9–20). Their structures were established from spectroscopic analysis. The clerodane diterpenoids 1–8 were evaluated for inhibition of nitric oxide (NO) production in LPS-activated RAW 264.7 macrophages. Compounds 1, 2, 5, 7 and 8 showed potent inhibitory effects, with IC50 values ranging from 32.19 to 48.85 μM, which is better than both the standard drugs indomethacin (154.5 μM) and dexamethasone (56.28 μM). [ABSTRACT FROM AUTHOR]

Polyalthia longifolia (Annonaceae family) is native to the drier areas of India and is locally called "Ashoka." It is also cultivated in Southeast Asia, Africa, Australia and New Zealand. Polyalthia longifolia is also known as Buddha tree, mast tree, cemetery tree, false Ashoka or green Champa. Generally, Polyalthia longifolia is viewed as a street tree because of its effectiveness in combating noise pollution. Macroscopically, the versatile Polyalthia longifolia can reach over 15.0 m high with symmetrical pyramidal growth and weeping pendulous branches. The term Polyalthia is derived from Greek roots, with "poly" meaning many and "althia" meaning cure, indicating that this plant has been used to treat various diseases/disorders. In traditional and indigenous systems of medicine, Polyalthia longifolia has been commonly used in the treatment of fever, helminthiasis, diabetes and various cardiac problems. Pharmacological investigations have shown that Polyalthia longifolia possesses significant biological and pharmacological activity, which may include antibacterial, antifungal, antitumor, anti-ulcer, antidiabetic and antioxidant properties. To date, more than 30 studies have analyzed extracts from bark, leaves, roots, seeds, etc. of the plant and reported a total of approximately 100 compounds, including steroids, flavonoids, clerodane diterpenes, cleroda-oic acids and alkaloids. In context of the broad medicinal potential of Polyalthia longifolia, this review compiles a detailed exploration of currently available knowledge of the phytochemical and their pharmacological properties of Polyalthia longifolia. Its potential applications in the treatment of various conditions are also discusseds. [ABSTRACT FROM AUTHOR]

In the present study, in silico predictions and molecular docking were performed on five clerodane diterpenes (1–5) from Polyalthia longifolia seeds to evaluate their potential as xanthine oxidase (XO) inhibitors. The initial screening was conducted by target prediction using TargetNet web server application and only compounds 3 and 4 showed a potential interaction with XO. Compounds 3 and 4 were subsequently subjected to in silico analyses on XO protein structure (PDB: 1N5X) using Schrödinger Release 2020–3 followed by structural modeling & molecular simulation studies to confirm the initial prediction result and identify the binding mode of these compounds to the XO. Molecular docking results revealed that compounds 3 (-37.3 kcal/mol) and 4 (-32.0 kcal/mol) binds more stably to XO than the reference drug allopurinol (-27.0 kcal/mol). Interestingly, two residues Glu 802 and Thr 1010 were observed as the two main H-bond binding sites for both tested compounds and the allopurinol. The center scaffold of allopurinol was positioned by some π-π stacking with Phe 914 and Phe 1009, while that of compounds 3 and 4 were supported by many hydrophobic interactions mainly with Leu 648, Phe 649, Phe 1013, and Leu 1014. Additionally, the docking simulation predicted that the inhibitory effect of compounds 3 and 4 was mediated by creating H-bond with particularly Glu 802, which is a key amino acid for XO enzyme inhibition. Altogether, in vitro studies showed that compounds 3 and 4 had better inhibitory capacity against XO enzyme with IC50 values significantly (p < 0.001) lower than that of allopurinol. In short, the present study identified cleroda-4(18),13-dien-15,16-olide as novel potential XO inhibitors, which can be potentially used for the treatment of gout. [ABSTRACT FROM AUTHOR]

• Parastrephia lucida fractions are rich in phenolic compounds, mainly flavonoids. • Some fractions exhibited an important in vitro and in vivo antioxidant activity. • P. lucida fractions showed a significant inhibition on hyaluronidase and xanthine oxidase. • P. lucida showed no toxicity or genotoxicity. • The results support the potential use of P. lucida in oxidative stress related disease. Parastrephia lucida (Meyen) Cabrera is an endemic species from the Argentinean Puna used in traditional medicine to relieve inflammation. To give scientific support to the ethnopharmacological claim, a bio-guided fractionation of a P. lucida extract was carried out according to its antioxidant activity (in vitro by different primary and secondary methodologies and in vivo on Caenorhabditis elegans) and its ability to inhibit pro-inflammatory enzymes (hyaluronidase and xanthine oxidase). Acute toxicity and genotoxicity of P. lucida were also studied by using Artemia salina and C. elegans bioassays, and Ames test, respectively. Compound characterization of P. lucida extracts and fractions was performed through UHPLC-quadrupole Orbitrap mass spectrometry. P. lucida total methanolic (MeOH) and dichloromethane (DCM) extracts (obtained from the partition of MeOH), showed high flavonoid contents (25.6 and 28.0 µg QE/mg DW) and significant inhibition of pro-inflammatory enzymes (IC 50 : 320.0 and 280.0 µg/mL on hyaluronidase, and IC 50 : 53.0 and 44.0 µg/mL on xanthine oxidase, respectively), as well as in vitro and in vivo antioxidant capacity. From DCM, fractions E and F, showed a lack of toxicity or genotoxic, inhibited the xanthine oxidase activity 4-fold than DCM extract, and exhibited high in vivo antioxidant activity, evidenced by the protection of C. elegans against oxidative damage caused by H 2 O 2 and Paraquat between 20 and 30 %. Besides, fractions E and F extended the nematode lifespan between 19 and 38%. Sixty-three metabolites, including several phenolic acids, coumarins, methoxylated flavonoids, tremetone derivates, and clerodane diterpenes, were accurately identified in the DCM fractions of P. lucida. This work not only scientifically supports P. lucida traditional use but also contributes to the search for new natural compounds aimed to treat processes related to inflammatory diseases, associated with oxidative stress. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Rationale: Clerodane‐type diterpenes from Casearia species show important pharmacological activites such as antitumor, antimicrobial and anti‐inflamatory. There are several mass spectrometry (MS)‐based methods for identification of diterpenes; however, there is still a lack of MS procedures capable of providing characteristic fragmentation pathways for a rapid and unambiguous elucidation of casearin‐like compounds. Methods: Casearin‐like compounds were investigated by electrospray ionization tandem mass spectrometry (ESI‐MS/MS). The fragmentation studies were carried out by tandem mass spectrometry in space (quadrupole time‐of‐flight (QTOF)) using different collision energies and also by tandem mass spectrometry in time (QIT) by selective isolation of product ions. Results: Casearin‐like compounds presented a predominance of sodium‐ and potassium‐cationized precursor ions. Both QIT and QTOF techniques provided sequential neutral losses of esters related to the R1 to R5 substituents linked to the nucleus of the clerodane diterpenes. The fragmentation pathway is initiated with a cleavage of the ester moieties R2 followed by the elimination of the ester groups R3, both losing neutral carboxylic acids. Using QIT, it was also possible to observe the cleavage of the ester groups R1 or R5 by MS4 experiments. Conclusions: Through a rational analysis of the fragmentation mechanisms of Casearia diterpenes it was possible to suggest an annotation strategy based on the sequential cleavages of the ester groups related to the R2, R3 and R5 substituents. These results will assist studies of the dereplication and metabolomics involving casearin‐like compounds present in complex extracts of Casearia species. [ABSTRACT FROM AUTHOR]

Covering January to December 2017; previous review Nat. Prod. Rep., 2017, 34, 1233–1243. This review covers the isolation and chemistry of diterpenoids from terrestrial as opposed to marine sources and includes labdanes, clerodanes, abietanes, pimaranes, kauranes, cembranes and their cyclization products. There are 228 references. [ABSTRACT FROM AUTHOR]

More than 20 natural products have been reported to modulate PCSK9-mediated cholesterol regulation, and small-molecule-derived proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors continue to be developed and identified. Here, twelve undescribed clerodane-type diterpenes (1 – 9 and 12 – 14) and two known compounds were isolated from the chloroform-soluble extract of the dried fruits of Casearia grewiifolia Vent. using a PCSK9 mRNA expression monitoring assay. Among the undescribed compounds, the stereochemistry of two diastereomeric grewiifolins A and B (1 and 2) were extensively elucidated using 2D Nuclear Overhauser Effect Spectroscopy (NOESY) experiments, excitation-sculptured indirect detection experiments (EXSIDE), interproton distance analyses, and computational calculations that included quantum chemical shift calculations combined with DP4+ analysis. All isolates were assessed for their inhibitory activity against PCSK9 and IDOL mRNA expression. Among the compounds tested, compound 3 inhibited PCSK9 and IDOL mRNA expression. [Display omitted] • Twelve undescribed diterpenes were isolated from Casearia grewiifolia. • The stereochemistry of 1 and 2 was assigned by DP4+ and interproton distance analyses. • The isolates were investigated for their PCSK9 inhibitory effects. [ABSTRACT FROM AUTHOR]

The Latin American medicinal plant carqueja got its name from a morphologically similar plant from the Iberian peninsula. The popular name came in general use to indicate all species from the section Caulopterae from the genus Baccharis, which are often difficult to distinguish. Phytochemical studies indicate that the different species from this section contain similar compound classes, especially essential oils, flavonoids and diterpenes, but much variation is encountered in relation to the individual compounds within the species. There are also some indications for the existance of different chemotypes within species. Recovered information from manuscripts, elaborated in the Jesuit missions, and originally authored by the Jesuit friar Pedro de Montenegro around 1710, indicate that carqueja was used by the Guarani indians of Southern Latin America for wound treatment. This traditional use was largely lost and nowadays the plant is mainly indicated for intestinal problems, as a tonic or for treatment of diabetes. It might be possible that this is caused by a confusion with quina, around 1800, which led to the alternative popular name "Quina de Condamine". The confusion about the identification of individual species persists up to today. In pharmacological studies performed with crude extracts, doubts arise about the species used and its phytochemical composition. Also in medicinal teas different species are used indiscriminantly leading to great differences in phytochemical profile. In this paper information about the phytochemistry, medicinal use, botanical specimens and nomenclature is extensively reviewed and recommendations for further studies and increased reproducibility of pharmacological studies are given. [ABSTRACT FROM AUTHOR]

16α-Hydroxycleroda-3,13(14)Z-dien-15,16-olide (4655K-09 or K-09) is a novel clerodane diterpene lactone reported for its anti-hyperlipidemic efficacy. The objective of the present study was to investigate the probable reversible metabolism of 4655K-09 and evaluate its effects on pharmacokinetic (PK) properties. The PK studies were carried out through intravenous (IV) bolus administration of 4655K-09 and K-9T in mice at a dose of 3, 6 and 12 mg/kg separately. The oral PK study of 4655K-09 was carried out at therapeutic dose of 25 mg/kg. The % AUC of metabolite converted to parent upon its administration was found to be 27.28 ± 2.67. The multi-compartmental interconversion model defined reversible and irreversible clearances along with volumes of distribution for parent and metabolite. The results emphasized that hydrolysis of lactone to acid was more efficient than back conversion to parent due to greater extent of irreversible elimination of acid. Further, the role of interconversion in pharmacokinetics of 4655K-09 was evaluated through secondary parameters like conversion coefficients of parent to metabolite (), metabolite to parent (: 0.019 ± 0.001), exposure enhancement (EE: 1.04 ± 0.006), and recycled fraction (RF: 0.042 ± 0.007), highlighted the minimal role of interconversion. The estimation of oral bioavailability remains unaffected when calculated through considering reversible metabolism. The present model-based interconversion pharmacokinetics of 4655K-09 in mice could be further extended to other species to support its development as anti-hyperlipidemic agent. [ABSTRACT FROM AUTHOR]

Abstract A phytochemical investigation of the stem barks of the Malaysian Croton oblongus Burm.f. (Syn. Croton laevifolius Blume) (Euphorbiaceae) yielded seven previously undescribed ent-neo- clerodane diterpenoids, laevifins A - G and the known crovatin (3). Structures were established by a combination of spectroscopic methods including HRESIMS, NMR spectroscopy and X-ray crystallography. The absolute configuration of crovatin and laevifins A-G was established by comparison of experimental ECD and theoretical TDDFT ECD calculated spectra. This is the first report on the occurrence of the sesquiterpenoid cryptomeridiol in a Croton species. In vitro cytotoxicity assays on laevifins A, B and G showed moderate activities against the MCF-7 cancer cell line (IC 50 102, 115 and 106 μ M, respectively) while β -amyrin and acetyl aleuritolic acid showed good anti-inflammatory activity on the LPS-induced NF-κB translocation inhibition in RAW 264.7 cells assay with IC 50 values of 23.5 and 35.4 μ g/mL, respectively. Graphical abstract Seven previously undescribed ent-neo- clerodane diterpenoids (1 , 2 , 4 - 8) were isolated from Croton oblongus Burm.f. Image 1 Highlights • The stem barks of Malaysian Croton oblongus Burm.f. (Euphorbiaceae) was investigated. • Seven previously undescribed ent-neo- clerodane diterpenoids, laevifins A - G were isolated. • The absolute configurations were determined using Electronic Circular Dichroism. • This is the first occurrence of the sesquiterpenoid cryptomeridiol in Croton. [ABSTRACT FROM AUTHOR]

Forty-three metabolites including several methoxylated flavonoids, tremetones, and ent-clerodane diterpenes were accurately identified for the first time in the ethanolic extract of P. quadrangularis by means of hyphenated UHPLC-quadrupole Orbitrap mass spectrometry, and seven isolated compounds were tested regarding gastroprotective activity using the HCl/EtOH-induced lesion model in mice. A new tremetone (compound 6) is reported based on spectroscopic evidence. The isolated clerodanes and tremetones showed gastroprotective activity in a mouse model, evidenced by compound 7 (p-coumaroyloxytremetone), which showed the highest gastroprotective activity (76%), which was higher than the control drug lansoprazole (72%). Our findings revealed that several constituents of this plant have gastroprotective activity, and particularly, p-coumaroyloxytremetone could be considered as a lead molecule to explore new gastroprotective agents. This plant is a rich source of biologically active tremetones and terpenoids which can support the ethnobotanical use of the plant. [ABSTRACT FROM AUTHOR]

Salvifarinin A ( 1 ), a rearrangement product of Languidulane-type clerodane diterpenoids with a 6/5/7 tricyclic ring skeleton fused with γ -lactone ring and furan ring, and two new biogenetically related diterpernoids, salvifarinins B ( 2 ) and C ( 3 ), were isolated from the aerial parts of Salvia farinacea . The absolute configuration of 1 was elucidated by extensive spectroscopic methods, and confirmed by single crystal X-ray diffraction and bio-inspired semisynthesis. The plausible biogenetic pathway was also proposed. Compound 2 displayed a potent effect on reducing hepatic steatosis. [ABSTRACT FROM AUTHOR]

New clerodane diterpenes, 12-epi-megalocarpodolide D (2) and an epimeric mixture of crotonolins A (3) and B (4), were isolated from the bark of Croton oligandrus following a bioassay-guided isolation protocol. Known compounds, megalocarpodolide D (1), 12-epi-crotocorylifuran (5), cluytyl-ferulate (6), hexacosanoyl- ferulate (7), vanillin (8), acetyl-aleuritolic acid (9) and lupeol (10), were also isolated. The structures of the isolated compounds (1–10) were elucidated by spectroscopic means. The cytotoxicity of compounds 1–10 was assessed against A549, MCF7, PC3 and PNT2 cell lines using the MTT assay. Compounds 1 and 2 showed moderate levels of activity against both A549 and MCF7 cells with 1 being the most active with IC50 values of 63.8 ± 13.8 and 136.2 ± 22.7 µM against A549 and MCF7 cells, respectively. The epimeric mixture of 3 and 4 was moderately active against A549 and PC3 cells (IC50 = 128.6 ± 31.0 and 111.2 ± 2.9 µM, respectively). [ABSTRACT FROM AUTHOR]

Five previously undescribed terpenoids (cracrosons D-H), including three clerodane diterpenoids, together with 16 known diterpenoids were isolated from Croton crassifolius (Euphorbiaceae). Cracroson D features a previously undescribed carbon skeleton with an unprecedented cyclobutane ring. Their structures, including their absolute configurations, were elucidated using spectroscopic and single-crystal X-ray diffraction analyses along with CD calculations. A plausible biogenetic pathway for cracroson D is also proposed, which was supported by the experimental results. Additionally, all of the compounds were evaluated in vitro for cytotoxicity against T24 and A549 cells using the CCK-8 method. [ABSTRACT FROM AUTHOR]

The phytochemical profile of essential oils and extracts from Casearia sylvestris leaves, flowers and fruits have been investigated here. Leaf and flower extracts were prepared by sonication and analyzed by thin-layer chromatography and high-performance liquid chromatography. The phenolic content was determined by ultraviolet spectrophotometry. Leaves, flowers, and fruits essential oils were extracted by hydrodistillation. The highest extracts yields were 20.3% (leaves) and 23.4% (flowers) with ethanol 70%. Essential oil extraction yields were 0.3% (leaves) and 0.1% (flowers and fruits). Bicyclogermacrene was the major component in all essential oil. Thin-layer chromatography suggests a chemical profile similar for leaves and flowers. The leaves and flowers phenolic contents were similar (14.0 and 15.0%, respectively). Chromatographic analyses indicated the predominance of casearin clerodane diterpenes in leaves (λmax 232-235), whereas in flowers diterpenes with a different standard diene in side-chain C13(16) and C14 (λmax 223-229). The different phytochemical profile of C. sylvestris flowers as compared to the leaves could be explored by the search for new bioactive components. This is the first report on the fruit and flower C. sylvestris essential oil composition. These data could be used as quality control of herbal medicine derived from C. sylvestris leaves. [ABSTRACT FROM AUTHOR]

Two new neo-clerodane derivatives, scutegalerins F and G, have been isolated from the acetone extract of the aerial parts of Scutellaria galericulata. The structures of the compounds were established by spectroscopic means and by comparison with the literature data of closely relative compounds. [ABSTRACT FROM AUTHOR]

The clerodane diterpene family possesses an impressive range of bioactivities and high synthetic challenge due to their unique amalgamation of rings, stereocenters, and oxygenation. Herein, we disclose the first total syntheses of three members, scaparvins B, C, and D, through a route fueled by several chemoselective and carefully orchestrated steps. One such operation is a tailored late-stage C-H functionalization converting a carboxylic acid into a lactone through the oxidation of a tertiary C-H bond under conditions that minimize epoxidation of an alkene. This step, among others, afforded critical functionality to complete the targets. In addition, use of an appropriate chiral catalyst with a Rawal diene renders the sequence enantioselective. [ABSTRACT FROM AUTHOR]

Context:Gymnosperma glutinosum(Spreng.) Less. (Asteraceae) is a bush used for the empirical treatment of pain, fever, and cancer. Anent-neo-clerodane diterpene (2-angeloylent-dihydrotumanoic acid; ADTA) was isolated fromG. glutinosum. Objective:This study evaluates the cytotoxic, anti-inflammatory, and antinociceptive effects of ADTA. Materials and methods:The cytotoxic effects of ADTA (1–350 μM) were evaluated using the MTT assay with human tumorigenic (SW-620, MDA-MB231, SKLU1, SiHa, and PC-3), and non-tumorigenic (HaCaT) cells for 48 h. Thein vitroanti-inflammatory effects of ADTA (0.23–460 μM) were assessed using murine peritoneal macrophages stimulated with LPS and estimating the levels of pro-inflammatory mediators for 48 h. The antinociceptive effects of ADTA (25–100 mg/kg p.o.) were evaluated using twoin vivomodels of chemical-induced nociception during 1 h. Results:ADTA lacked cytotoxic activity (IC50> 100 μM) on tumorigenic cells. In non-tumorigenic cells (HaCaT), ADTA exerted low cytotoxic effects (IC50 = 273 μM). ADTA, at concentrations of 115 μM or higher, decreased the release of pro-inflammatory mediators. The maximum antinociceptive effects of ADTA in the acetic acid-induced abdominal constrictions by ADTA was found at 100 mg/kg (63%), whereas in the formalin test at phase 1 and phase 2, ADTA (100 mg/kg) decreased the licking time by 47 and 71%, respectively. Conclusion:The results indicate that ADTA, obtained fromG. glutinosum, exerts moderatein vitroanti-inflammatory andin vivoantinociceptive effects, but lacks cytotoxic effects on human cancer cells. [ABSTRACT FROM PUBLISHER]

NMR and single crystal X-ray diffraction analysis of seven clerodanes from Mexican Salvia species was performed. We focused on clerodanes with tertiary hydroxyl group at C-4, C-8, and C-10, in which the establishment of absolute configuration around these chiral centers is nontrivial and the 13 C NMR signals can be misassigned. In addition, the analysis by 1 H NMR in aprotic solvent allowed us to establish a common pattern that correlates the chemical shift with the position of the hydroxyl groups, which constitute a good methodology for future structural elucidation of these kinds of compounds. The obtained data allowed us to establish the absolute configuration of five of these diterpenes and the structural revision of salvimicrophyllin D ( 7 ). [ABSTRACT FROM AUTHOR]

A stereocontrolled approach to the cis-decalin framework of clerodane diterpenes and biologically active quinone sesquiterpenes is reported. Starting from an inexpensive optically pure tetrahydroindanone, Birch reductive alkylation builds two new contiguous chiral centers--one of which is quaternary and all-carbon-substituted. Also featured is a highly regioselective diazoalkane--carbonyl homologation reaction to prepare the 6,6-bicyclic skeleton. Therein, the utility of Sc(OTf)3 as a mild catalyst for formal 1C insertion in complex settings is demonstrated. [ABSTRACT FROM AUTHOR]

A new clerodane diterpene, Caseargrewiin M (1), and one known compound (2) were isolated from fresh ripe fruits of Casearia grewiifolia. The structures of all isolated compounds were evaluated on the basic 1D (¹H and 13C) and 2D NMR (COSY, HSQC, HMBC and NOESY) spectral data. All compounds were examined cytotoxicity with five human cancer cell lines, Hep-G2 (hepatocarcinoma), SW620 (colon adenocarcinoma), Chago-K1 (undifferentiated lung carcinoma), KATO-III (gastric carcinoma), and BT474 (breast ductal carcinoma). Isolated compounds showed broad cytotoxicity against five human cancer cell lines with IC50 values between 0.90-6.30 µg/mL. [ABSTRACT FROM AUTHOR]

1. The metabolism of the anti-inflammatory diterpenoid polyandric acid A (PAA), a constituent of the Australian Aboriginal medicinal plantDodonaea polyandra, and its de-esterified alcohol metabolite, hydrolysed polyandric acid A (PAAH) was studiedin vitrousing human liver microsomes (HLM) and recombinant UDP-glucuronosyltransferase (UGT) and cytochrome P450 (CYP) enzymes. 2. Hydrolysis of PAA to yield PAAH occurred upon incubation with HLM. Further incubations of PAAH with HLM in the presence of UGT and CYP cofactors resulted in significant depletion, with UGT-mediated depletion as the major pathway. 3. Reaction phenotyping utilising selective enzyme inhibitors and recombinant human UGT and CYP enzymes revealed UGT2B7 and UGT1A1, and CYP2C9 and CYP3A4 as the major enzymes involved in the metabolism of PAAH. 4. Analysis of incubations of PAAH with UDP-glucuronic acid-supplemented HLM and recombinant enzymes by UPLC/MS/MS identified three glucuronide metabolites. The metabolites were further characterised by β-glucuronidase and mild alkaline hydrolysis. The acyl glucuronide of PAAH was shown to be the major metabolite. 5. This study demonstrates thein vitrometabolism of PAA and PAAH and represents the first systematic study of the metabolism of an active constituent of an Australian Aboriginal medicinal plant. [ABSTRACT FROM PUBLISHER]

Systematic analyses of plants that are used in traditional medicine may lead to the discovery of novel cytotoxic secondary metabolites. Diterpene possesses multiple bioactivities; here, epoxy clerodane diterpene (ECD) was isolated from Tinospora cordifolia (Willd.) stem and shown potential antiproliferative effect in MCF-7 human breast cancer cells. The antiproliferative effect of ECD on MCF-7 cells was systematically analyzed by cell and nuclear morphology, alterations in oxidative stress, and the expression of tumor suppressor and mitochondria-mediated apoptosis-related genes. We found that the IC 50 value of ECD was 3.2 μM at 24 h and 2.4 μM at 48 h. We observed that the cytotoxicity of ECD was specific to MCF-7 cells, whereas ECD was nontoxic to normal Vero and V79 cells. ECD significantly triggered intracellular ROS generation even from the lower doses of 0.6 and 1.2 μM; and it is relative to higher dose of 2.4 μM. Further, we used 0.6 μM, 1.2 μM and 2.4 μM as experimental doses to analyze the relative dose-dependent effects. Nuclear staining revealed that cells treated with the 2.4 μM dose exhibited characteristic apoptotic morphological changes and that 46% of the cells were apoptotic and 4% were necrotic after 48 h. ECD significantly increased the expression of mitochondria-dependent apoptotic pathway-related genes after 48 h; we observed significantly ( p ≤ 0.05) increased expression of CYP1A, GPX, GSK3β and TNF-α and downregulated expression of NF-κB. ECD also increased the expression of tumor suppressor genes such as Cdkn2A, Rb1 and p53. In addition, we observed that ECD treatment significantly ( p ≤ 0.001) upregulated the expression of apoptotic genes such as Bax, cas-3, cas-8, cas-9 and p21 and downregulated the expression of BCL-2, mdm2 and PCNA. In conclusion, ECD regulates the expression of Cdkn2A, p53 and mdm2 and induces apoptosis via the mitochondrial pathway in MCF-7 human breast cancer cells. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the most common type of liver cancer, and treatment options for HCC are limited. In addition, the discovery of new natural compounds with anti-hepatocarcinoma activity is attracting increasing attention. For this reason, phytochemical investigation of Croton crassifolius led to the isolation of 17 diterpenoids, including three new clerodane diterpenoids, named crassifolius A-C ( 1 – 3 ), along with 14 known ones ( 4 – 17 ). Their structures were established by 1D, 2D NMR, HR-ESI-MS, detailed calculated electronic circular dichroism (ECD) spectra and the assistance of quantum chemical predictions (QCP) of 13 C NMR chemical shifts. The cytotoxicities of all these compounds against human liver cancer lines (HepG2 and Hep3B) were determined. Among them, compound 1 exhibited good cytotoxicity with IC 50 value of 17.91 μM against human liver tumor cells Hep3B. Following further studies of the anti-tumor mechanism of compound 1 -induced cell growth inhibition, we found that compound 1 caused apoptotic cell death in Hep3B cells by detecting morphologic changes and Western blotting analysis. [ABSTRACT FROM AUTHOR]

Teucrium polium L. is a species with ancient ethno-botanical uses for its anti-inflammatory action which is mainly due to the phenolics content. On the other side, the presence of neo -clerodanes, which exert hepatotoxic action, may explain why in recent years the medicinal uses of this species have drastically diminished. In this paper we report on the isolation of a new natural neo -clerodane diterpenoid, namely 20- O -acetyl-teucrasiatin ( 2 ), together with other twelve relevant compounds in the fields of chemotaxonomy and ethnomedicine. Nevertheless, the total absence of iridoids and in particular of the chemotaxonomic markers of the family and of the genus itself, may reveal an intraspecific variability of T. polium with different chemotypes which may contain or not iridoids. [ABSTRACT FROM AUTHOR]

Seven new clerodane diterpenoids, dodovisnoids A−G ( 1 – 7 ), were isolated from Dodonaea viscosa . The structures of these compounds were identified by extensive spectroscopic data. The absolute configurations of 1 , 2 , and 6 were assigned by X-ray crystallographic analysis. Compound 1 is an unprecedented clerodane diterpenoid possessing a new carbon skeleton that could biogenetically derive from 5,10-secoclerodane. Compounds 2 – 5 are rare cyclopropyl-modified clerodanes and 6 is the first dinor-clerodane featuring an alkynyl moiety. Compounds 4 – 7 showed antiviral activity against herpes simplex virus type 1 (HSV-1) in vitro. [ABSTRACT FROM AUTHOR]

A new clerodane was isolated from Dodonaea ceratocarpa and obtained in appreciable quantities (0.5% w/w plant). A variety of reactions on this clerodane provided access to a range of new derivatives, including cationic skeletal rearrangements and reduction reactions with lanthanide salt additives. [ABSTRACT FROM AUTHOR]

Ten new ( 1 - 10 ) and seventeen known ( 11 - 27 ) neo -clerodane diterpenoids substituted with nicotinoyloxyl were isolated from the plant Scutellaria barbata and their structures were established by extensive spectroscopic analysis. Chemoreversal effects of these neo -clerodane diterpenoids on multidrug resistance were evaluated in breast cancer multidrug-resistant MCF-7/ADR cells that overexpress P-glycoprotein. Four compounds ( 11 , 14 , 16 , and 18 ) exhibited better chemoreversal abilities than the classical P-gp inhibitor verapamil and the most potent compound 11 reduced IC 50 value of adriamycin in MCF-7/ADR cells from 58.8 μ M to 1.3 μ M. Mechanistic investigations showed that compound 11 reversed multidrug resistance through suppressing the activity of P-gp and restraining the expression of P-glycoprotein. In the present study, the structure–activity relationships of neo -clerodane diterpenoids were also discussed. [ABSTRACT FROM AUTHOR]

Biotransformation of the antifungal compound 16-oxocleroda-3,13(14)E-dien-15-oic acid (1) isolated fromPolyalthia longifolialeaves was achieved byRhizopus stoloniferin broth medium containing the substrate at the sublethal concentration of 0.06 mg ml−1. A novel derivative, 18-hydroxy-16-oxocleroda-3,13(14)E-dien-15-oic acid (2) was isolated after 4 d of incubation. Minimum inhibitory concentration (MIC) was determined against 11 fungal pathogens of clinical and agricultural importance. The biotransformed compound showed lower MIC values than the natural parent compound. The study showed that the fungusR. stoloniferhas the potential to hydroxylate a natural fungicidal clerodane diterpene at allylic position to produce a novel hydroxylated derivative with enhanced antifungal activity. [ABSTRACT FROM PUBLISHER]

Covering January to December 2015. Previous review; Nat. Prod. Rep., 2015, 32, 1654–1663. This review covers the isolation and chemistry of diterpenoids from terrestrial as opposed to marine sources and includes labdanes, clerodanes, abietanes, pimaranes, kauranes, cembranes and their cyclization products. There are 214 references. [ABSTRACT FROM AUTHOR]

Covering: 1990 to 2015 The clerodane diterpenoids are a widespread class of secondary metabolites and have been found in several hundreds of plant species from various families and in organisms from other taxonomic groups. These substances have attracted interest in recent years due to their notable biological activities, particularly insect antifeedant properties. In addition, the major active clerodanes of Salvia divinorum can be used as novel opioid receptor probes, allowing greater insight into opioid receptor-mediated phenomena, as well as opening additional areas for chemical investigation. This article provides extensive coverage of naturally occurring clerodane diterpenes discovered from 1990 until 2015, and follows up on the 1992 review by Merritt and Ley in this same journal. The distribution, chemotaxonomic significance, chemical structures, and biological activities of clerodane diterpenes are summarized. In the cases where sufficient information is available, structure activity relationship (SAR) correlations and mode of action of active clerodanes have been presented. [ABSTRACT FROM AUTHOR]

Forty-three metabolites including several methoxylated flavonoids, tremetones, and ent-clerodane diterpenes were accurately identified for the first time in the ethanolic extract of P. quadrangularis by means of hyphenated UHPLC-quadrupole Orbitrap mass spectrometry, and seven isolated compounds were tested regarding gastroprotective activity using the HCl/EtOH-induced lesion model in mice. A new tremetone (compound 6) is reported based on spectroscopic evidence. The isolated clerodanes and tremetones showed gastroprotective activity in a mouse model, evidenced by compound 7 (p-coumaroyloxytremetone), which showed the highest gastroprotective activity (76%), which was higher than the control drug lansoprazole (72%). Our findings revealed that several constituents of this plant have gastroprotective activity, and particularly, p-coumaroyloxytremetone could be considered as a lead molecule to explore new gastroprotective agents. This plant is a rich source of biologically active tremetones and terpenoids which can support the ethnobotanical use of the plant.

The genus Aristolochia,an important source of physiologically active compounds that belong to different chemical classes, is the subject of research in numerous pharmacological and chemical studies. This genus contains a large number of terpenoid compounds, particularly diterpenes. This work presents a compilation of the 13C-NMR data of 57 diterpenoids described between 1981 and 2007 which were isolated from Aristolochia species. The compounds are arranged skeletonwise in each section, according to their structures, i.e., clerodane, labdane, and kaurane derivatives. A brief discussion on the 13C chemical shifts of these diterpenes is also included.