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Two new clerodane diterpenoids (1 and 2), a new pyran-2-one derivative (3), along with five known compounds (4‒8), were isolated from Croton crassifolius. Notably, crassifolin X (1) is a novel clerodane diterpenoid, characterized with a peculiar δ-lactone core being formed between C-1 and C-4. Their structures, including absolute configurations, were established on the basis of spectroscopic methods (UV, IR, HRESIMS and NMR), and circular dichroism experiments. In addition, all compounds were evaluated for their anti-neuroinflammatory activities based on the expression of TNF-α and IL-6 levels on LPS-induced BV2 cells, and compounds 1‒3 and 5 showed potential anti-neuroinflammatory activity.

Callintegers A (

The PI3K/AKT and MAPK/ERK pathways are frequently mutated in metastatic melanoma. In a screen of over 2500 plant extracts, the dichloromethane extract of Ericameria nauseosa significantly inhibited oncogenic activity of AKT in MM121224 human melanoma cells. This extract was analyzed by analytical HPLC, and the column effluent was fractionated and tested for activity to generate the so-called HPLC-based activity profile. Compounds eluting within active time-windows of the chromatogram were subsequently isolated in a larger scale to afford 11 flavones (1-11), four flavanones (12-15), two diterpenes (16, 17), and a seco-caryophyllene (18). All isolated compounds were tested for activity, whereby only flavonoids were found active. Of these, flavones were shown to be more active than the flavanones. The most potent flavone was compound 9, that was displaying an IC

Hepatocellular carcinoma (HCC) is a major subtype of primary liver cancer with a high mortality rate. Pyroptosis and autophagy are crucial processes in the pathophysiology of HCC. Searching for efficient drugs targeting pyroptosis and autophagy with lower toxicity is useful for HCC treatment. Mallotucin D (MLD), a clerodane diterpenoid from

Herbal medicines are still widely practiced in Kurdistan Region-Iraq, especially by people living in villages on mountainous regions. Among plants belonging to the genus

Introduction Tolerance (TOL) and physical dependence (PD) constitute important limitations of opioid therapy. The aim of our study was to validate research tools to investigate TOL and PD and to characterize the interactions between opioid (OR) and cannabinoid (CB) receptors in these processes in the GI tract. Methods TOL was assessed through the comparison of morphine ability to inhibit electrically evoked smooth muscles contractility in the mouse ileum that was previously incubated with/without morphine for 1 h. To evaluate the PD, the ileum was incubated with morphine for 10 min, then challenged with naloxone to induce withdrawal response (WR). The OR/CB interactions were evaluated using mixed agonist (PR-38) and AM-251 (CB1 antagonist). Results The inhibitory effect of morphine on ileal contractions was weaker in tissue incubated with this opioid than in tissue incubated without opioid. The opposite was noted for PR-38. In tissues exposed to morphine, but not to PR-38, naloxone induced a WR. The blockage of CB1 receptors with AM-251 before the addition of PR-38 resulted in a naloxone-induced WR. Conclusion The co-activation of OR and CB reduced development of TOL and PD to opioids in the mouse GI tract and mixed OR/CB agonists are promising alternative to currently used opioid drugs.

A concise enantioselective total synthesis of the neoclerodane diterpene (−)‐salvinorin A is reported. The stereogenic center at C‐12 was installed by catalytic asymmetric propargylation with excellent enantioselectivity, and the remaining six stereogenic centers were set up highly diastereoselectively under substrate control. As for our previous synthesis of racemic salvinorin A, two intramolecular Diels‐Alder reactions were applied to generate the tricyclic core. A chemoselective Mitsunobu inversion of a syn 1,2‐diol allowed for further streamlining of the original reaction sequence by two steps. Overall, (−)‐salvinorin A was synthesized in only 16 steps starting from 3‐furaldehyde with 1.4 % total yield. Furthermore, an alternative intramolecular Diels‐Alder strategy employing a 2‐bromo‐1,3‐diene moiety was investigated., A divine sage: The potent KOR agonist (−)‐salvinorin A was synthesized in only sixteen steps by modification of our previous route to the racemic title compound. Transition to asymmetric synthesis succeeded by a highly enantioselective propargylation to install the stereogenic center at C‐12. Shortening of the original reaction sequence by two steps was finally achieved using a chemoselective Mitsunobu esterification of a cyclic syn 1,2‐diol. Furthermore, an alternative intramolecular Diels‐Alder strategy employing a 2‐bromo‐1,3‐diene moiety was investigated.

The trans-clerodanes and sesquiterpene (hydro)quinones are a growing class of natural products that exhibit a wide range of biological activities. Although they are different types of natural products, some of them feature the same trans-decalin core structure. Here, we report the total syntheses of two members of trans-clerodanes, five members of sesquiterpene (hydro)quinones as well as the proposed structure of dysidavarone D via a modular synthetic route. A bioinspired tail-to-head cyclization strategy was developed to syntheses of the trans-decalin architectures by using two diastereochemically complementary radical polyene cyclization reactions catalyzed by Ti(III) and mediated by Mn(III), respectively. The different types of side chains were introduced by challenging nickel catalyzed reductive couplings of sterically hindered alkyl halides. The synthesis of the proposed dysidavarone D proved a wrong structural assignment of the natural product.

Callicarpnoids A-C (1-3), three new ent-clerodane diterpenoid dimers formed via a [4 + 2] hetero Diels-Alder cycloaddition, appeared as a third example of this type of dimers, were isolated from the stems of Callicarpa arborea Roxb.. Their structures were elucidated by comprehensive spectroscopic analysis, and the absolute configurations were confirmed by single-crystal X-ray diffraction and electronic circular dichroism (ECD) calculations, as well as DP4 + analysis. Cytotoxicity test in two cell lines indicated that compounds 2 and 3 had significant cytotoxic effect against breast cancer cell (MCF-7) and colorectal cancer cell (HCT-116) with ICsub50/subranging from 5.2 to 7.2 μM, comparable to those of the positive control. Furthermore, the western blot analysis revealed that the protein expression levels of Bax were increased following compounds 2 and 3 treatment, whereas the expression levels of caspase 8, caspase 3, caspase 9 and Bclsub2/subwere decreased in a dose-dependent manner, indicating that compounds 2 and 3 may induce apoptosis via both intrinsic and extrinsic pathways in MCF-7 and HCT-116 cells.

The present work introduces a high-performance thin-layer chromatography (HPTLC)-direct bioautography method using the Gram-positive plant pathogenic bacterium, Rhodococcus fascians. The screening and isolation procedure comprised of a non-targeted high-performance thin-layer chromatography-effect-directed analysis (HPTLC-EDA) against Bacillus subtilis, B. subtilis subsp. spizizenii, R. fascians, and Aliivibrio fischeri, a targeted HPTLC-mass spectrometry (MS), and bioassay-guided column chromatographic (preparative flash and semi-preparative HPLC) fractionation and purification. The developed new separation methods enabled the discovery of four bioactive cis-clerodane diterpenes, solidagoic acid H (1), solidagoic acid E (2), solidagoic acid I (3), and solidagoic acid F (4), in the n-hexane extract of giant goldenrod (Solidago gigantea Ait.) leaf for the first time. These compounds were identified by 1D and 2D nuclear magnetic resonance (NMR) spectroscopy. The initially used HPTLC method (chloroform - ethyl acetate - methanol 15:3:2, V/V/V) was changed (to n-hexane - isopropyl acetate - methanol - acetic acid 29:20:1:1, V/V/V/V) to achieve the separation of the closely related isomer pairs (1-2 and 3-4). Compounds 1 and 3 exhibited moderate antibacterial activity against the Gram-positive B. subtilis subsp. spizizenii and R. fascians bacterial strains in microdilution assays with half-maximal inhibitory concentration (IC

Made available in DSpace on 2021-06-25T10:47:52Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-02-01 Casearia sylvestris is an outstanding representative of the Casearia genus. This representability comes from its distinctive chemical profile and pharmacological properties. This species is widespread from North to South America, occurring in all Brazilian biomes. Based on their morphology, 2 varieties are recognized: C. sylvestris var. sylvestris and C. sylvestris var. lingua. Despite the existence of data about their chemical composition, a deeper understanding of the specialized metabolism correlation and variation in respect to environmental factors and its repercussion over their biological activities was still pending. In this study, an UHPLC-DAD-based metabolomics approach was employed for the investigation of the chemical variation of 12 C. sylvestris populations sampled across 4? Brazilian biomes and ecotones. The correlation between infraspecific chemical variability and the cytotoxic and antioxidant activities was achieved by multivariate data analysis. The analyses showed that C. sylvestris var. lingua prevailed at Cerrado areas, and it was correlated with lower cytotoxic activity and high level of glycosylated flavonoids. Among them, narcissin and isorhamnetin-3- O-α -L-rhamnopyranosyl-(1 → 2)- α -L-arabinopyranoside showed good correlation with the antioxidant activity. Conversely, C. sylvestris var. sylvestris prevailed at the Atlantic Forest areas, and it was associated with high cytotoxic activity and high content of clerodane diterpenoids. Different casearins showed good correlation (R 2= 0.3?-?0.70) with the cytotoxic activity. These findings highlighted the great complexity among different C. sylvestris populations, their chemical profile, and the related biological activities. Consequently, it can certainly influence the medicinal properties, as well as the quality and efficacy, of C. sylvestris phytomedicines. Institute of Chemistry Department of Biochemistry and Organic Chemistry São Paulo State University (UNESP), CEP 14800-060, Rua Prof. Francisco Degni 55 Natural Products Laboratory Institute of Biology Leiden University Natl. Inst. of Alternative Technol. for Detection Toxicological Assess. Removal of Micropollutants and Radioactive Substances Araraquara Agronomic Institute of Campinas Herbarium IAC Department of Biophysics and Physiology Laboratory of Experimental Cancerology Federal University of Piauí Department of Physiology and Pharmacology Faculty of Medicine Federal University of Ceará Institute of Chemistry Department of Biochemistry and Organic Chemistry São Paulo State University (UNESP), CEP 14800-060, Rua Prof. Francisco Degni 55

An EtOAc extract of

One of the key areas of interest in pharmacognosy is that of the diterpenoids; many studies have been performed to identify new sources, their optimal isolation and biological properties. An important source of abietane-, pimarane-, clerodane-type diterpenoids and their derivatives are the members of the genus

A new clerodane diterpene, named 6α-hydroxy-3,13E-clerodien-15-oic acid (1), together with a known clerodane diterpene (2), four known labdane diterpenes (3-6), a triterpenoid (7), a known steroid (8), and two benzenoid compounds (9 and 10) were isolated from Detarium microcarpum Guill.Perr. The structures of all obtained compounds were determined by chemical properties and spectroscopic evidence, accompanied by comparisons with data in the literature. Electronic circular dichroism (ECD) was performed for compounds 1-4 to confirm the absolute configuration. Compounds 1-3 and 8-10 were evaluated for the protective effect on osteoblasts. Compound 1 was observed to increase the proliferation of dexamethasone (DEX)-treated MC3T3-E1 cells significantly at 1 μM, which was comparable with the positive control geniposide at 10 μM. The results were further confirmed by flow cytometry analysis. In addition, compound 1 increased the level of alkaline phosphatase (ALP) and mineralization in osteoblasts inhibited by DEX. Moreover, Compound 9 (vanillic acid) showed a pronounced inhibition (IC

Current common analgesics are mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects. However, ligands exhibiting dual agonism to the opioid receptors, such as to mu and kappa, or to mu and delta, have been suggested to temper undesirable adverse effects while retaining analgesic activity. Herein we report an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold via an ester linker. In vitro studies showed that many of these compounds have dual agonism on kappa and mu opioid receptors. In vivo studies on the lead dual kappa and mu opioid receptor agonist demonstrated supraspinal thermal analgesic activity while avoiding anxiogenic effects in male mice, thus providing further strong evidence in support of the therapeutic advantages of dual opioid receptor agonists over selective opioid receptor agonists.

The generation of the quaternary stereocenter at the C9 position of salvinorin A precursors by the Claisen rearrangement was investigated. The required allyl alcohol was prepared from a Wieland-Miescher ketone using a known γ-hydroxylation, reduction of the enone double bond, cyanohydrin formation, and elimination, yielding an unsaturated nitrile. A two-step reduction led to the required allyl alcohol. The subsequent Johnson-Claisen rearrangement provided a mixture of two diastereomeric 1,4-unsaturated esters in a ratio of around 2.6 : 1. The major isomer could be converted to a key intermediate of the Hagiwara synthesis of salvinorin A.

Salvinorin A (SA) is a κ-opioid receptor agonist and atypical dissociative hallucinogen found in Salvia divinorum. Despite the resurgence of hallucinogen studies, the effects of κ-opioid agonists on human brain function are not well-understood. This placebo-controlled, within-subject study used functional magnetic resonance imaging for the first time to explore the effects of inhaled SA on strength, variability, and entropy of functional connectivity (static, dynamic, and entropic functional connectivity, respectively, or sFC, dFC, and eFC). SA tended to decrease within-network sFC but increase between-network sFC, with the most prominent effect being attenuation of the default mode network (DMN) during the first half of a 20-min scan (i.e., during peak effects). SA reduced brainwide dFC but increased brainwide eFC, though only the former effect survived multiple comparison corrections. Finally, using connectome-based classification, most models trained on dFC network interactions could accurately classify the first half of SA scans. In contrast, few models trained on within- or between-network sFC and eFC performed above chance. Notably, models trained on within-DMN sFC and eFC performed better than models trained on other network interactions. This pattern of SA effects on human brain function is strikingly similar to that of other hallucinogens, necessitating studies of direct comparisons.

Pain remains a very pervasive problem throughout medicine. Classical pain management is achieved through the use of opiates belonging to the mu opioid receptor (MOR) class, which have significant side effects that hinder their utility. Pharmacologists have been trying to develop opioids devoid of side effects since the isolation of morphine from papaver somniferum, more commonly known as opium by Sertürner in 1804. The natural products salvinorin A, mitragynine, and collybolide represent three nonmorphinan natural product-based targets, which are potent selective agonists of opioid receptors, and emerging next-generation analgesics. In this work, we review the phytochemistry and medicinal chemistry efforts on these templates and their effects on affinity, selectivity, analgesic actions, and a myriad of other opioid-receptor-related behavioral effects.

Natural metabolites with their specific bioactivities are being considered as a potential source of materials for pharmacological studies. In this study, we successfully isolated and identified five known clerodane diterpenes, namely 16-oxo-cleroda-3,13(14)E-dien-15-oic acid (1), 16-hydroxy-cleroda-3,13-dien-15-oic acid (2), 16-hydroxy-cleroda-4(18),13-dien-16,15-olide (3), 3α,16α-dihydroxy-cleroda-4(18),13(14)Z-dien-15,16-olide (4), and 16α-hydroxy-cleroda-3,13(14)Z-dien-15,16-olide (5) from the methanolic extract of seeds of Polyalthia longifolia. Initially, all the isolated metabolites were investigated for COX-1, COX-2, and 5-LOX inhibitory activities using the standard inhibitory kits. Of which, compounds 3, 4, and 5 exhibited to be potent COX-1, COX-2, and 5-LOX inhibitors with the IC50 values similar or lower to those of the reference drugs. To understand the underlying mechanism, these compounds were subjected to molecular docking on COX-1, COX-2, and 5-LOX proteins. Interestingly, the in silico study results were in high accordance with in vitro studies where compounds 3, 4, and 5 hits assumed interactions and binding pattern comparable to that of reference drugs (indomethacin and diclofenac), as a co-crystallized ligand explaining their remarkable dual (COX/LOX) inhibitor actions. Taken together, our findings demonstrated that compounds 3, 4, and 5 functioned as dual inhibitors of COX/5-LOX and can contribute to the development of novel, more effective anti-inflammatory drugs with minimal side-effects.

Kappa-opioid receptor (KOR) agonists are antinociceptive but have side effects that limit their therapeutic utility. New KOR agonists have been developed that are fully efficacious at the KOR but may produce fewer or reduced side effects that are typical of KOR agonists. We determined behavioral profiles for typical and atypical KOR agonists purported to differ in intracellular-signaling profiles as well as a mu-opioid receptor (MOR) agonist, oxycodone, using a behavioral scoring system based on Novak et al. (Am J Primatol 28:124-138, 1992, Am J Primatol 46:213-227, 1998) and modified to quantify drug-induced effects (e.g., Duke et al. J Pharmacol Exp Ther 366:145-157, 2018). Six adult male rhesus monkeys were administered a range of doses of the typical KOR agonists, U50-488H (0.0032–0.1 mg/kg) and salvinorin A (0.00032–0.01 mg/kg); the atypical KOR agonists, nalfurafine (0.0001–0.001 mg/kg) and triazole 1.1 (0.01–0.32 mg/kg); the MOR agonist, oxycodone (0.0032–0.32 mg/kg); and as controls, cocaine (0.032–0.32 mg/kg) and ketamine (0.32–10 mg/kg). For time-course determinations, the largest dose of each KOR agonist or MOR agonist was administered across timepoints (10–320 min). In mixture conditions, oxycodone (0.1 mg/kg) was followed by KOR-agonist administration. Typical KOR agonists produced sedative-like and motor-impairing effects. Nalfurafine was similar to typical KOR agonists on most outcomes, and triazole 1.1 produced no effects on its own except for reducing scratch during time-course determinations. In the mixture, all KOR agonists reduced oxycodone-induced scratching, U50-488H and nalfurafine reduced species-typical activity, and U50-488H increased rest/sleep posture. Atypical “biased” KOR agonists produce side-effect profiles that are relatively benign (triazole 1.1) or reduced (nalfurafine) compared to typical KOR agonists.

Objective Premature and ill neonates undergo painful but medically necessary procedures while hospitalized. Although opiate drugs are administered as analgesics, problems associated with their side effects, tolerance, and potential dependence necessitate research into alternative pain-relieving medications. Here we test two plant-derived compounds in infant rats: sinomenine, which targets the Mas-related G-protein-coupled receptor member X2 opioid receptor; and salvinorin A, which is a κ opioid receptor agonist. In adult animals both sinomenine and salvinorin A are analgesic, but neither has been tested in infants. Methods We used the formalin and thermal plantar tests in rats 7 and 21 days of age (PN7 and PN21) for behavioral signs of pain. In addition, brain sections were stained using Fos immunohistochemistry to examine patterns of brain activation in the midbrain periaqueductal gray and the paraventricular nucleus of the hypothalamus. Results Sinomenine was analgesic in both the formalin and thermal tests on animals 21 days of age. At PN7 only the highest dose elevated response latencies in the thermal test and there were no effects of sinomenine in the formalin test. Analysis of Fos expression in the sinomenine-treated animals showed no drug effect, in contrast to the behavioral results. Salvinorin A was analgesic in the formalin test only at the highest dose at 21 days of age but not in the thermal test at either age. Conclusion The increased modest effectiveness of sinomenine in older animals and the minimum salvinorin A drug effect suggest that the compounds act on sites that develop during the preweaning period (sinomenine) or after weaning (salvinorin A).

RATIONALE: Combinations of mu and kappa opioid receptor (KOR) agonists have been proposed as potential analgesic formulations with reduced abuse liability. The current studies extend previous work by investigating the typical KOR agonist, salvinorin A, and the atypical KOR agonist, nalfurafine, as deterrents of oxycodone self-administration using a progressive-ratio (PR) schedule of reinforcement. METHODS: In separate experiments, adult male rhesus monkeys (N=4/experiment) were trained under a PR schedule of reinforcement to self-administer cocaine (0.1 mg/kg/injection) and saline on alternating days. Oxycodone (0.01–0.1 mg/kg/injection) alone and combined with salvinorin A (Experiment 1; 0.006, 0.012 mg/kg/injection) or nalfurafine (Experiment 2; 0.0001–0.00032 mg/kg/injection) were tested within the alternating cocaine and saline baseline. The mechanism of nalfurafine’s effects on oxycodone self-administration was investigated via pretreatment with the KOR antagonist, nor-Binaltorphimine (nor-BNI; 10 mg/kg; i.m.). RESULTS: All subjects self-administered oxycodone alone above saline levels at sufficiently large doses, and combining salvinorin A or nalfurafine with oxycodone reduced the mean number of injections per session to saline levels (Experiment 1) or to levels that were significantly lower than oxycodone alone (Experiment 2). The ability of nalfurafine to reduce oxycodone self-administration was reversed by pretreatment with nor-BNI. CONCLUSIONS: These results demonstrate that KOR agonists, including the clinically-used KOR agonist, nalfurafine, can punish self-administration of a prescription opioid analgesic, oxycodone, in rhesus monkeys, and that nalfurafine’s punishing effect is KOR dependent. Combinations of KOR agonists with prescription opioids may have reduced abuse liability.

Covering: 2000 to 2020 The hallucinogenic diterpene salvinorin A potently and selectively agonizes the human kappa-opioid receptor (KOR). Its unique attributes-lack of a basic nitrogen, rapid brain penetrance, short half-life-combined with the potential of KOR as an emerging target for analgesics have stimulated extensive medicinal chemistry based on semi-synthesis from extracts of Salvia divinorum. Total synthesis efforts have delivered multiple, orthogonal routes to salvinorin A, its congeners and related analogs with the goal of optimizing its activity towards multiple functional endpoints. Here we review total syntheses of the salvinorin chemotype and discuss outstanding problems that synthesis can address in the future.

Salvia semiatrata Zucc. (Lamiaceae) is a species used as a tranquilizer and to relieve pain in folk medicine in Santiago Huauclilla, Oaxaca, Mexico. To evaluate the antinociceptive and anxiolytic-like effects of S. semiatrata extracts and identify a bioactive metabolite. The extracts were obtained by maceration of S. semiatrata aerial parts using solvents in increasing polarity (hexane, ethyl acetate and methanol). A neo-clerodane diterpene was extracted from the ethyl acetate fraction using open column chromatography. Identification of this metabolite was performed by crystallography, 1H NMR, 13C NMR, ATR-IR, ECD, MS and elemental analysis. The antinociceptive activity was explored using the writhing and formalin tests. Whereas, the anxiolytic-like responses were analysed in the open-field, hole-board and plus-maze tests. All the treatments were administered using oral gavage in male CD1 mice and explored 30 min after administration of the individual extracts (300 mg/kg) or the compound 1 (0.1, 1 or 10 mg/kg). All the extracts produced significant reduction in the nociceptive and anxiety-like behaviour compared to mice treated with the vehicle (0.5% tween 80 in saline solution). The spectroscopic analysis corroborated the presence of the neo-clerodane diterpene 7-keto-neoclerodan-3,13-dien-18,19:15,16-diolide (1), as partial responsible of the antinociceptive and anxiolytic-like effects, which produced a dose-dependent response in the writhing test with an ED50=4.15 mg/kg. Discussion and conclusions: These results reinforce the medicinal properties of S. semiatrata in folk medicine, where participation of a neo-clerodane diterpene was evidenced in the inhibitory central nervous system activity of this species.

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.

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Phytochemical investigation of the leaves and twigs of Callicarpa cathayana led to the isolation of six new clerodane diterpenoids, cathayanalactones A–F (1–6), together with seven analogues (7–13). Their structures were established by extensive NMR analyses together with experimental and calculated ECD spectra analyses. Compounds 1, 2, 3, 7 and 11 showed inhibitory activities on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells.

Over the past decades, antibiotic resistance has grown to a point where orthogonal approaches to combating infections caused by resistant bacteria are needed. One such approach is the development of non-microbicidal small molecules that potentiate the activity of conventional antibiotics, termed adjuvants. The diterpene natural product 12(S),16ε-Dihydroxycleroda-3,13-dien-15,16-olide, which we refer to as (−)-LZ-2112, is known to synergize with oxacillin against methicillin-resistant Staphylococcus aureus (MRSA). To explore this activity, (−)-LZ-2112 was synthesized and the structure confirmed through X-ray analysis. Preliminary structure-activity relationship studies following the synthesis of several analogues identified key structural elements responsible for activity and indicate that scaffold simplification is possible. A preliminary mode of action study suggests mecA plays a role in the adjuvant activity of (−)-LZ-2112.

Pyroptosis is a programmed-inflammatory cell death, which leads to release of inflammatory cellular contents and formation of inflammation. Uncontrollable pyroptosis can result in serious immune diseases, such as cytokine release syndrome (CRS), sepsis, disseminated intravascular coagulation (DIC), and acute organ damage, including acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI). Members of the Callicarpa genus are significant raw materials for traditional Chinese medicine, widely used for analgesia, hemostasis, and anti-inflammation. Previously, we have reported some ent-clerodane diterpenoids from Callicarpa arborea, shown potent inhibitory effects against pyroptosis. In this study, we went on investigating this kind of diterpenoids, and yielded 66 ent-clerodane diterpenoids, including 52 new compounds, from Callicarpa arborea. Their structures featured with a 5/6- (1-25) or a 6/6- (26-66)-fused double-ring scaffolds, were elucidated using spectroscopic data, electrostatic circular dichroism (ECD) and X-ray diffraction analyses. Screening for the inhibitory activity against pyroptosis by detecting of IL-1β secretion in J771A.1 cells, revealed 28 compounds with an IC

A phytochemical investigation to obtain bioactive substances as lead compounds or agents for anti-inflammatory led to the obtainment of eleven previously undescribed clerodane diterpenoids, named caseatardies A-K (1-11), and four known clerodane diterpenoids (12-15) from the twigs and leaves of Casearia tardieuae. The structural elucidation of these clerodane diterpenoids was based on 1D and 2D-NMR spectroscopy (COSY, HSQC, HMBC and ROESY) as well as high resolution mass spectrometry (HR-ESI-MS). The relative configurations were defined by ROESY correlations. The anti-inflammatory activity of all the isolated compounds was screened and compound 15 decreased LDH level in a dose-dependent manner, showing IC

One new clerodane-type diterpenoid, together with one known, was isolated from the leaves and twigs of

Renoprotectors are highly demanded due to environmental nephrotoxic factors.

In the search for new natural resources showing plant disease control effects, we found that the methanol extract of

Objectives: The toxicity of chemotherapeutic anticancer drugs is a serious issue in clinics. Drug discovery from edible and medicinal plants represents a promising approach towards finding safer anticancer therapeutics. Justicia insularis T. Anderson (Acanthaceae) is an edible and medicinal plant in Nigeria. This study aims to discover cytotoxic compounds from this rarely explored J. insularis and investigate their underlying mechanism of action. Methods: The cytotoxicity of the plant extract was evaluated in human ovarian cancer cell lines and normal human ovarian surface epithelia (HOE) cells using a sulforhodamine B assay. Bioassay-guided isolation was carried out using column chromatography including HPLC, and the isolated natural products were characterized using GC-MS, LC-HRMS, and 1D/2D NMR techniques. Induction of apoptosis was evaluated using Caspase 3/7, 8, and 9, and Annexin V and PI based flow cytometry assays. SwissADME and SwissTargetPrediction web tools were used to predict the molecular properties and possible protein targets of identified active compounds. Key finding: The two cytotoxic compounds were identified as clerodane diterpenoids: 16(α/β)-hydroxy-cleroda-3,13(14)Z-dien-15,16-olide (1) and 16-oxo-cleroda-3,13(14)E-dien-15-oic acid (2) from the Acanthaceous plant for the first time. Compound 1 was a very abundant compound (0.7% per dry weight of plant material) and was shown to be more potent than compound 2 with IC50 values in the micromolar range against OVCAR-4 and OVCAR-8 cancer cells. Compounds 1 and 2 were less cytotoxic to HOE cell line. Both compounds induced apoptosis by increasing caspase 3/7 activities in a concentration dependent manner. Compound 1 further increased caspase 8 and 9 activities and apoptosis cell populations. Compounds 1 and 2 are both drug like, and compound 1 may target various proteins including a kinase. Conclusions: Clerodane diterpenoids (1 and 2) in J. insularis were identified as cytotoxic to ovarian cancer cells via the induction of apoptosis, providing an abundant and valuable source of hit compounds for the treatment of ovarian cancer.

The bioactivity-guided isolation on the Scutellaria barbata extract resulted in the purification of four undescribed neo -clerodane diterpenoids, scuttenlines A-D ( 1-4 )，alone with 20 known diterpenoids ( 5-24 ). The chemical structures of them were elaborated by extensive spectroscopic means, including 1D, 2D-NMR and HR-MS. The anti-inflammatory potential ability of 1 - 24 was screened in lipopolysaccharide-stimulated mouse RAW 264.7 cells. Scuttenline C (IC 50 = 1.9 µM) and 18 (IC 50 = 3.7 µM) exhibited potent activity to inhibit NO production.

A new neo-clerodane diterpenoid, salvihispin H (1), and six known ones (2-7) were identified from the aerial parts of Salvia hispanica L. The structure and absolute configuration of 1 were elucidated by extensive analysis of spectroscopic (1 H, 13 C, and 2D NMR, and HR-ESI-MS) and single-crystal X-ray diffraction data. The anti-diabetic effects of salvihispin H (1) and salvifaricin (2) were evaluated in diabetic db/db mice. The data showed that 1 and 2 could significantly reduce fasting blood glucose level and improve insulin resistance, and compound 1 exerted glucose-lowering effect more quickly than metformin. In addition, 1 and 2 could also reduce serum TG level in db/db mice. These results demonstrated that compounds 1 and 2 could be considered as potent candidates for the therapy of type 2 diabetes mellitus (T2DM).

Scopariusicides D-M (1-10), ten new ent-clerodane-based meroditerpenoids with a cyclobutane-fused γ/δ-lactone core, were isolated from Isodon scoparius. Their structures were determined by comprehensive analysis of spectroscopic data, single-crystal X-ray diffraction, chemical transformation, and TDDFT ECD calculation. A plausible biosynthetic pathway of 1-10 was proposed in which the asymmetrical cyclobutane ring was formed via a crossed "head-to-tail" intermolecular [2 + 2] cycloaddition in anti/syn facial approaches between an ent-clerodane lactone and a cis-4-hydroxycinnamic acid. Bioactivity evaluation manifested that 5 exhibited significant neuroprotective effect against corticosterone-induced injury in PC12 cells, while 6 and 7 exhibited moderate immunosuppressive activity against human T cell proliferation stimulated by anti-CD3/anti-CD28 mAb.

Scutellaria genus, a member of the Lamiaceae family, distributed worldwide and known as skullcaps, contains a wide range of pharmacologically active constituents including flavonoids and diterpenes. There are different classes of diterpenes in the plant kingdom, of which many have medicinal applications. Scutellaria spp. contain neo-clerodane diterpenes, a large group of naturally occurring specialized metabolites found in both plant species and in organisms from other taxonomic groups, such as fungi, bacteria, and marine sponges. Although many phytochemical studies have been established reporting interesting specialized diterpene structures from Scutellaria spp., there has not been a comprehensive study reviewing these compounds. Hence, the present review reports on natural diterpenoids from the Scutellaria genus and their pharmacological activities. For this purpose, the scientific databases including Scopus, PubMed, and Google Scholar were searched using the keywords "Scutellaria" and "Diterpenes" or "Diterpenoids". The literature review showed that up to now, more than 300 diterpenes have been isolated and reported from the Scutellaria genus, belonging to neo-clerodane scaffolds. Anticancer, antifeedant, phytotoxic, antimicrobial, and nitric oxide production inhibitory activities are the most reported properties for the diterpenoids from the Scutellaria genus. Diterpenes of Scutellaria spp. have therapeutic potentials to be used for the treatment of different diseases. Further phytochemical, pharmacological, and clinical studies are required in this regard.

Scospirosins A (

Phytochemical investigation of the leaves and twigs of Croton yanhuii led to the isolation of seven highly modified nor-clerodane diterpenoids (1-7), including three new ones, croyanoids A-C (1-3), along with four known analogues (4-7). Compound 1 incorporates a 5,12-epoxy ring, forming a unique cage-like, 6/6/6/5-fused tetracyclic ring system. Their structures were established by extensive spectroscopic analysis, and the absolute configurations of 1-4 were determined by a combination of circular dichroism (CD) analysis and single-crystal X-ray diffraction. All compounds were tested in an array of bioassays, but were inactive. Crotoeurin A (7), a nor-clerodane dimer with a high yield of 0.2‰ isolated in current study, was considered as a chemotaxonomic marker for this species.

Dietary supplements based on Teucrium chamaedrys L. subsp. chamaedrys aerial parts were banned, due to the hepatotoxicity of furan-containing neo-clerodane constituents. Indeed, the plant leaf content in phenolic compounds could be further exploited for their antioxidant capability. Accordingly, bio-guided fractionation strategies have been applied, obtaining seven partially purified extracts. These latter were chemically investigated through 1D and 2D NMR techniques and tested for their antiradical, reducing and cytotoxic capability. Data acquired highlighted that, through a simple phytochemical approach, a progressive neo-clerodane depletion occurred, while maximizing phenylethanoid glycosides in alcoholic fractions. Thus, although the plant cannot be used as a botanical remedy as such, it is suggested as a source of healthy compounds, pure or in mixture, to be handled in pharmaceutical, nutraceutical and/or cosmeceutical sectors.

Early brain injury (EBI) refers to the direct injury to the brain during the first 72 h after subarachnoid hemorrhage (SAH), which is one of the major causes for the poor clinical outcome after SAH. In this study, we investigated the effect and the related mechanism of Salvinorin A (SA), a selective kappa opioid receptor agonist, on EBI after SAH. SA was administered by intraperitoneal injection at 24 h, 48 h and 72 h after SAH. The volume of lateral ventricle was measured by magnetic resonance imaging (MRI). The neuronal morphological changes and the apoptotic level in CA1 area of hippocampus were observed by Nissl and TUNEL staining respectively. Protein expression of p-PI3K, p-Akt, p-IKKα/β, p-NF-κB, FoxO1, Bim, Bax and Cleaved-caspase-3 was measured to explore the potential mechanism. We found that SA alleviated the neuronal morphological changes and apoptosis in CA1 area of hippocampus. The mechanism might be related to the increased protein expression of p-PI3K/p-Akt, which accompanied by decreased expression of p-IKKα/β, p-NF-κB, FoxO1, Bim, Bax and Cleaved-caspase-3 in the hippocampus. Thus, therapeutic interventions of SA targeting the PI3K/Akt pathway might be a novel approach to ameliorate EBI via reducing the apoptosis and inflammation after SAH.