Artemyriantholides A-K, guaiane-type sesquiterpenoid dimers from Artemisia myriantha var. pleiocephala and their antihepatoma activity.

Artemyriantholides A-K (1-11) as well as 14 known compounds (12-25) were isolated from Artemisia myriantha var. pleiocephala (Asteraceae). The structures and absolute configuration of compounds 2 and 8-9 were confirmed by the single crystal X-ray diffraction analyses, and the others were elucidated by MS, NMR spectral data and electronic circular dichroism calculations. All compounds were chemically characterized as guaiane-type sesquiterpenoid dimers (GSDs). Compound 1 was the first example of the GSD fused via C-3/C-11' and C-5/C-13' linkages, and compounds 2 and 5 were rare GSDs containing chlorine atoms. Eleven compounds showed obvious inhibitory activity in HepG2, Huh7 and SK-Hep-1 cell lines by antihepatoma assay to provide the IC50 values ranging from 7.9 to 67.1 µM. Importantly, compounds 5 and 8 exhibited the best inhibitory activity with IC50 values of 14.2 and 18.8 (HepG2), 9.0 and 11.5 (Huh7), and 8.8 and 11.3 µM (SK-Hep-1), respectively. The target of compound 5 was predicted to be MAP2K2 by a computational prediction model. The interaction between compound 5 and MAP2K2 was conducted to give docking score of -9.0 kcal/mol by molecular docking and provide KD value of 43.7 µM by Surface Plasmon Resonance assay.

Antiproliferative Activities of Cynaropicrin and Related Compounds against Cancer Stem Cells.

Glioblastoma (GBM) has a high mortality rate despite the availability of various cancer treatment options. Although cancer stem cells (CSCs) have been associated with poor prognosis and metastasis, and play an important role in the resistance to existing anticancer drugs and radiation; no CSC-targeting drugs are currently approved in clinical practice. Therefore, the development of antiproliferative agents against CSCs is urgently required. In this study, we evaluated the antiproliferative activities of 21 sesquiterpenoids against human GBM U-251 MG CSCs and U-251 MG non-CSCs. Particularly, the guaianolide sesquiterpene lactone cynaropicrin (1) showed strong antiproliferative activity against U-251 MG CSCs (IC50 = 20.4 µM) and U-251 MG non-CSCs (IC50 = 10.9 µM). Accordingly, we synthesized six derivatives of 1 and investigated their structure-activity relationships. Most of the guaianolide sesquiterpene lactones with the α-methylene-γ-butyrolactone moiety showed antiproliferative activities against U-251 MG cells. We conclude that the 5,7,5-ring and the α-methylene-γ-butyrolactone moiety are both important for antiproliferative activities against U-251 MG cells. The results of this study suggest that the α,ß-unsaturated carbonyl moiety, which has recently become a research hotspot in drug discovery, is the active center of 1. Therefore, we consider 1 as a potential lead for developing novel drugs targeting CSCs.

Guaianolide sesquiterpenes and their activity from Artemisia mongolica.

Seven undescribed sesquiterpenes, including three dimeric guaianolide sesquiterpenes artemongolides G-I (1-3) and four sesquiterpene lactones artemanomalide D-G (16-19), along with seventeen known compounds isoabsinthin (4), absinthin (5), 11-eptabsinthin (6), 11, 11'-bis-epiabsinthin (7), 10', 11'- epiabsinthin (8), anabsinthin (9), isoanabsinthin (10), absinthin D (11), anabsin (12), caruifolin D (13), gnapholide (14), caruifolin C (15), 1ß(R),10ß(S)-dihydroxy-3-oxo-11ß (S)H-4,11(13)-guaien-6α(S),12-olide (20), 1α,6α,8α-trihydroxy-5α,7ßH-guaia-3,10(14),11(13)-trien-12-oic acid (21), 1α,6α,8α-trihydroxy-5α,7ßH-guaia-3,9,11(13)-trien-12-oic acid (22), argyinolide J (23), artabsinolide A (24) were isolated from the plant Artemisia mongolica. The structures were determined by interpreting NMR, HRESIMS and ECD data. The X-ray crystal structure of 4, 7 and 8 were reported for the first time. In the anti-vitiligo activity test, compounds 2, 7, 12, 23 and 24 demonstrated activity in promoting melanogenesis at a concentration of 50 µM in B16 cells, with 8-methoxypsoralan (8-MOP) as a positive control. Further research on the mechanism revealed that artemongolides H (2) enhance the expression of MITF and TRPs by upregulating p-Akt and p-GSK-3ß, leading to an increase in ß-catenin content in the cell cytoplasm. Subsequently, ß-catenin translocates into the nucleus, resulting in melanogenesis. The results supported the regulation of melanogenesis by artemongolide H (2) through the Akt/GSK3ß/ß-catenin signaling pathway. The anti-inflammatory results demonstrated that compounds 4, 5, 6, 9 and 14 can inhibit the upregulation of IL-6 mRNA and CCL2 mRNA expression. Compound 12 specifically inhibited the upregulation of IL-6 mRNA expression. These compounds exhibited significant anti-inflammatory activities. The activity results revealed that these sesquiterpene compounds have the potential to become lead compounds for the treatment of vitiligo and inflammatory diseases.

Glaucatotones A-I: Guaiane-type sesquiterpenoids from the roots of Lindera glauca with anti-inflammatory activity.

Glaucatotones A - I, nine new guaiane-type sesquiterpenoids, along with two reported compounds, namely (1ß,5ß)-1-hydroxyguaia-4(15),11(13)-dieno-12,5-lactone (10) and pseudoguaianelactone C (11), were isolated from the roots of Lindera glauca. The structures and absolute configurations of these compounds were elucidated by extensive spectroscopic analyses, single-crystal X-ray diffraction, and comparison of experimental and calculated electronic circular dichroism (ECD) data. Structurally, glaucatotone A (1) is characterized as a dihomosesquiterpenoid with an unprecedented 5/5/7/6 ring system. A pair of enantiomers, (±)-glaucatotone B (2a/2b), represent the first rearranged norsesquiterpenoid with a (cyclopentylmethyl)cyclohexane skeleton. 3 is defined as a dinorsesquiterpenoid possessing a 5/7/5 ring system. 4-6 are three guaiane-type norsesquiterpenoids. In vitro bioactivity, 2a selectively inhibited Bcap-37 with IC50 value of 5.60 µM, and 9 selectively inhibited Du-145 with IC50 value of 5.52 µM. The anti-inflammatory activity of 1-9 were tested, and of these compounds, 1, 2a, 2b and 7 exhibited potent inhibitory effects.

In silico toxicologic profile and in vivo trypanocidal activity of estafietin, a sesquiterpene lactone isolated from Stevia alpina Griseb.

Chagas disease is an infection caused by the protozoan Trypanosoma cruzi, affecting 6-8 million people worldwide. Only two drugs are available for its treatment, having a limited efficacy and adverse side-effects. Estafietin is a sesquiterpene lactone isolated from Stevia alpina with in vitro activity against T. cruzi and low cytotoxicity against mammalian cells. The aim of this work was to predict the toxicologic profile of estafietin by in silico methods and assess its in vivo activity on a murine model of Chagas disease. Estafietin showed low toxicity according to pkCSM web tool and passed the PAINS filter from PAINS-remover web server. The treatment of infected mice with 1 mg/Kg/day of estafietin for five consecutive days administrated by intraperitoneal route significatively decreased parasitemia levels and reduced inflammatory infiltrates and myocyte damage on muscle tissue. These results suggest that estafietin had effect both on acute and chronic stages of the infection.

Anti-inflammatory potential of some eudesmanolide and guaianolide sesquiterpenes.

Ten sesquiterpene lactones isolated from Anvillea garcinii (Burm.f.) DC ethanolic extract were assessed for their anti-inflammatory potential by myeloperoxidase (MPO) activity assignment, and mice paw swelling model. 3α,4α-10ß-trihydroxy-8α-acetyloxyguaian-12,6α-olide (1), epi-vulgarin (3), 9a-hydroxyparthenolide (4), garcinamine C (7), garcinamine D (8), garcinamine E (9), and 4, 9-dihydroxyguaian-10(14)-en-12-olide (10) showed explicit anti-inflammatory activity in rodent paw edema and MPO assignment. The findings of this study showed that the α-methylene γ-lactone moiety does not always guarantee an anti-inflammatory effect, but the presence of proline at the C3 of the lactone ring improves the binding of sesquiterpene lactones with MPO isoenzymes, resulting in a more potent inhibition.

Six undescribed guaianolide-type sesquiterpenes from the aerial parts of Daphne penicillata.

Six undescribed guaianolide sesquiterpenes (1-6) were obtained from the aerial parts of Daphne penicillata. Their structures and absolute configuration were elucidated by HRESIMS, NMR analyses, ECD calculations and single-crystal X-ray diffraction analysis. Structurally, all compounds possess the typical 5,7-fused system of 8,12-guaianolides and this guaianolide-type was first reported to be isolated from Daphne penicillata. All compounds (1-6) were evaluated for anti-inflammatory and cytotoxic activity. Among them, compounds 1 and 5 showed moderate inhibitory effects on LPS-induced NO production in BV2 cells and 4 displayed potential inhibition against Hep3B cells with an IC50 value of 7.33 µM.

Highly oxygenated guaiane-type sesquiterpene lactones from Artemisia sacrorum and their antihepatoma activity.

The ethanol and EtOAc extracts of Artemisia sacrorum exhibited inhibitory effect against HepG2, Huh7, and SK-Hep-1 cell lines with inhibitory ratios of 65.5%, 28.1%, 84.6%, and 93.5%, 82.0%, 89.0% at 200 µg/mL. Twenty-three undescribed guaiane-type sesquiterpene lactones, artemisacrolides A‒W, were isolated from A. sacrorum under the guidance of antihepatoma activity. Their structures were elucidated by spectral data (HRESIMS, IR, UV, 1D and 2D NMR), ECD calculations, and a single-crystal X-ray diffraction. Artemisacrolides A‒U were guaiane-type sesquiterpene lactones possessing α-methylene-γ-lactone and containing acetoxyl groups at C-8, and artemisacrolides V and W represented the first report from the genus Artemisia with a 1,10-rearranged guaiane-type sesquiterpene lactone. Antihepatoma assay suggested that artemisacrolides A‒U demonstrated better inhibitory activity in Huh7 and SK-Hep-1 cells than those of HepG2 cells. Among them, nine compounds exhibited significant inhibitory activity against Huh7 cells with IC50 values of 8.2-14.3 µM, superior or equal to that of sorafenib; seven compounds demonstrated obvious activity against SK-Hep-1 cells with IC50 values of 13.5-19.2 µM, which were equivalent to that of sorafenib. Artemisacrolides B and E were the most active ones in three human hepatoma cell lines with IC50 values of 21.9, 8.2, 16.9 and 22.6, 9.0, 17.3 µM.

Micheliolide prevents estrogen deficiency-induced bone loss via inhibiting osteoclast bone resorption.

Osteoporosis is one of the major health problems characterized by decreased bone density and increased risk of fractures. Nowadays, the treating strategies against osteoporosis are efficient, but still have some drawbacks. Micheliolide, a guaianolide sesquiterpene lactone isolated from Michelia compressa and Michelia champac, has been reported to have anti-inflammatory effects. Here, our data suggest that Micheliolide could protect mice from ovariectomy induced bone loss. According to the Micro-CT scan and histomorphometry quantification data, Micheliolide treatment inhibits excessive osteoclast bone resorption without affecting bone formation in estrogen deficiency mice. Consistently, our data suggest that Micheliolide could inhibit osteoclastogenesis in vitro. Additionally, we confirmed that Micheliolide inhibits osteoclasts formation via inhibiting P38 MAPK signaling pathway, and P79350 (a P38 agonist) could rescue this effect. In summary, our data suggest that Micheliolide could ameliorate estrogen deficiency-induced bone loss via attenuating osteoclastogenesis. Hence, Micheliolide could be used as a novel anti-resorptive agent against osteoporosis.

Artemongolins A-K, undescribed germacrane-guaiane sesquiterpenoid dimers from Artemisia mongolica and their antihepatoma activities.

Artemongolins A-K (1-11), which are undescribed sesquiterpenoid dimers, were obtained from Artemisia mongolica and characterized through comprehensive spectral data, including HRESIMS, IR, 1D and 2D NMR, and ECD calculations. The absolute configurations of compounds 1, 4, and 7 were undoubtedly determined by a single-crystal X-ray crystallography. Artemongolins A-K (1-11) featured a rare 5/7/5/5/5/10 hexacyclic system composed of a germacrene and a guaianolide by a fused 2-oxaspiro[4,4]nonane-1-one ring system. Antihepatoma evaluation against three human hepatoma cell lines demonstrated that the most active compounds 5 and 6 displayed inhibitory activity with IC50 values of 88.6 and 57.0 (HepG2), 59.1 and 26.4 (Huh7), and 67.5 and 32.5 (SK-Hep-1) µM, respectively.

An extensive pharmacological evaluation of novel anti-nociceptive and IL-6 targeted anti-inflammatory guaiane-type sesquiterpenoids from Cinnamomum migao H. W. Li through in-depth in-vitro, ADMET, and molecular docking studies.

Guaiane-type sesquiterpenoids are most prevalent in the genus Cinnamomum. Hence this study investigates the structures, anti-nociceptive and IL-6 targeted anti-inflammatory potential of three novels C-14 guaiane-type sesquiterpenoids and two new monoterpenoids, isolated from Cinnamomum migao. The structures were precisely confirmed and characterized through the modern chromatographic and spectroscopic techniques of HRESIMS, 1D NMR, 2D NMR, experimental circular dichroism (ECD), and calculated (ECD). Novel sesquiterpenoids 1 and 2 exhibited significant anti-inflammatory activities against the NO production and pro-inflammatory cytokines. Their IC50 values were determined as 9.52 and 13.42 µΜ against IL-6 mRNA, respectively. Similarly, subcutaneous injection of n-BuT and EA extracts showed a dose-dependent suppression of formalin-induced tonic biting/licking responses during the tonic antinociceptive phase. Furthermore, absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis of guaiane-type sesquiterpenoids 1 and 2 displayed that both compounds have a high level of GIT absorption, with a high zone of safety for cardiac and hepatotoxicity and no inhibition of cytochromes. In addition, molecular docking and simulation studies strengthen the anti-inflammatory potential of sesquiterpene 2 which showed a good binding affinity with IL-6 protein. Overall the inclusive results showed that the extracts and newly isolated guaiane-type sesquiterpenoids from C. migao will provide new evidence for the traditional use of this species to treat inflammation and nociception.

Cinnamigones A-C, three highly oxidized guaiane-type sesquiterpenes with neuroprotective activity from Cinnamomum migao.

Cinnamigones A-C, three undescribed highly oxidized guaiane-type sesquiterpenes were isolated from the fruits of Cinnamomum migao. Cinnamigone A (1), structurally artemisinin-like, is a natural 1,2,4-trioxane caged endoperoxide with an unprecedented tetracyclic 6/6/7/5 ring system. Compounds 2-3 are classic guaiane sesquiterpene featuring different epoxy units. Guaiol (4) is considered to be the precursor of 1-3 in the biosynthesis pathway hypothesis. The planar structures and configurations of cinnamigones A-C were elucidated by spectral analysis, HRESIMS, X-ray crystallography and ECD calculations. Evaluation of the neuroprotective activity of 1-3 on N-methyl-ᴅaspartate (NMDA) toxicity was demonstrated that compounds 1-2 exhibited moderate neuroprotective activity against NMDA-induced neurotoxicity.

Guaiane-Type Sesquiterpenes from the Stems of Fissistigma oldhamii.

Two new guaiane-type sesquiterpenes dysodensiols J and L, one new natural product dysodensiol K together with four known biogenetically related guaiane-type sesquiterpenes were isolated from the stems of Fissistigma oldhamii. Their structures were elucidated by detailed analysis of NMR, HR-ESI-MS, IR and Optical rotations data. Compound 1 contains an uncommon five-membered ether ring. The inhibitory effect of all compounds on the proliferation of primary synovial cells was evaluated. Compound 3 showed inhibitory activity with an IC50 value of 6.8 µM. Compounds 5-7 exhibited moderate inhibitory activity with IC50 values of 23.8, 26.6, and 27.1 µM, respectively.

Guaiazulene and related compounds: A review of current perspective on biomedical applications.

BACKGROUND: Thousands of people worldwide pass away yearly due to neurological disorders, cardiovascular illnesses, cancer, metabolic disorders, and microbial infections. Additionally, a sizable population has also been impacted by hepatotoxicity, ulcers, gastroesophageal reflux disease, and breast fissure. These ailments are likewise steadily increasing along with the increase in life expectancy. Finding innovative therapies to cure and consequently lessen the impact of these ailments is, therefore, a global concern. METHODS AND MATERIALS: All provided literature on Guaiazulene (GA) and its related compounds were searched using various electronic databases such as PubMed, Google Scholar, Web of Science, Elsevier, Springer, ACS, CNKI, and books via the keywords Guaiazulene, Matricaria chamomilla, GA-related compounds, and Guaiazulene analogous. RESULTS: The FDA has approved the bicyclic sesquiterpene GA, commonly referred to as azulon or 1,4-dimethyl-7-isopropylazulene, as a component in cosmetic colorants. The pleiotropic health advantages of GA and related substances, especially their antioxidant and anti-inflammatory effects, attracted a lot of research. Numerous studies have found that GA can help to manage various conditions, including bacterial infections, tumors, immunomodulation, expectorants, diuretics, diaphoresis, ulcers, dermatitis, proliferation, and gastritis. These conditions all involve lipid peroxidation and inflammatory response. In this review, we have covered the biomedical applications of GA. Moreover, we also emphasize the therapeutic potential of guaiazulene derivatives in pre-clinical and clinical settings, along with their underlying mechanism(s). CONCLUSION: GA and its related compounds exhibit therapeutic potential in several diseases. Still, it is necessary to investigate their potential in animal models for various other ailments and establish their safety profile. They might be a good candidate to advance to clinical trials.

Two new sesquiterpenes from Xylopia vielana.

Two new sesquiterpenes (1-2) and six known analogues (3-8) were isolated from the branches and leaves of Xylopia vielana Pierre. The structures of the new compounds were identified by analyzing 1 D and 2 D NMR data and HRESIMS data, combined with induced and calculated circular dichroism experiments. In addition, compounds 1-4, 7 and 8 showed notable nitric oxide (NO) inhibitory effects (IC50 < 10 µM) on the model of the lipopolysaccharide (LPS)-activated RAW 264.7 macrophages.

Guaianolide Derivatives from the Invasive Xanthium spinosum L.: Evaluation of Their Allelopathic Potential.

Ziniolide, xantholide B (11α-dihydroziniolide), and 11ß-dihydroziniolide, three sesquiterpene lactones with 12,8-guaianolide skeletons, were identified as volatile metabolites from the roots of Xanthium spinosum L., an invasive plant harvested in Corsica. Essential oil, as well as hydrosol and hexane extracts, showed the presence of guaianolide analogues. The study highlights an analytical strategy involving column chromatography, GC-FID, GC-MS, NMR (1D and 2D), and the hemi-synthesis approach, to identify compounds with incomplete or even missing spectral data from the literature. Among them, we reported the 1H- and 13C-NMR data of 11ß-dihydroziniolide, which was observed as a natural product for the first time. As secondary metabolites were frequently involved in the dynamic of the dispersion of weed species, the allelopathic effects of X. spinosum root's volatile metabolites were assessed on seed germination and seedling growth (leek and radish). Essential oil, as well as hydrosol- and microwave-assisted extracts inhibited germination and seedling growth; root metabolite phytotoxicity was demonstrated. Nevertheless, the phytotoxicity of root metabolites was demonstrated with a more marked selectivity to the benefit of the monocotyledonous species compared to the dicotyledonous species. Ziniolide derivatives seem to be strongly involved in allelopathic interactions and could be the key to understanding the invasive mechanisms of weed.

Guaiane-type sesquiterpenoids with various ring skeletons from Daphne bholua uncovered by molecular networking and structural revisions of previously reported analogues.

The genus Daphne is a treasure-house of secondary metabolites with various biological effects, which inspired Daphne bholua being fully investigated phytochemically and biologically for the first time. Here, seven undescribed guaiane-type sesquiterpenoids (1-7) along with thirteen known analogues (8-20) were targeted and isolated from D. bholua using molecular networking. Their chemical structure and configurations were established via NMR spectroscopy analysis, NMR and ECD calculations, Snatzke's method, along with single-crystal X-ray diffraction technique. Moreover, two pairs of sesquiterpene isomers, either with prominent biological properties or with unprecedented skeleton, were revised by means of computer-assisted structure elucidation, chemical shift calculator using deep learning, etc. The inhibitory potentials of all isolates against acetylcholinesterase were evaluated in vitro and in silico.

Englerin A Rewires Phosphosignaling via Hsp27 Hyperphosphorylation to Induce Cytotoxicity in Renal Cancer Cells.

Englerin A (EA) is a small-molecule natural product with selective cytotoxicity against renal cancer cells. EA has been shown to induce apoptosis and cell death through cell-cycle arrest and/or insulin signaling pathways. However, its biological mode of action or targets in renal cancer remains enigmatic. In this study, we employed advanced mass spectrometry-based phosphoproteomics approaches to identify EA's functional roles in renal cancer. We identified 10,940 phosphorylation sites, of which 706 sites exhibited EA-dependent phosphorylation changes. Integrated analysis of motifs and interaction networks suggested activation of stress-activated kinases including p38 upon EA treatment. Of note, a downstream target of p38, Hsp27, was found to be hyperphosphorylated on multiple sites upon EA treatment. Among these, a novel site Ser65 on Hsp27, which was further validated by targeted proteomics, was shown to be crucial for EA-induced cytotoxicity in renal cancer cells. Taken together, these data reveal the complex signaling cascade that is induced upon EA treatment and importantly provide insights into its effects on downstream molecular signaling.

Benzobicyclic ketones, cycloheptenone oxide derivatives, guaiane-type sesquiterpenes, and alkaloids isolated from Taraxacum mongolicum Hand.-Mazz.

Ten previously undescribed compounds, including two benzobicyclic ketones, one cycloheptenone oxide derivative, three guaiane-type sesquiterpenes, and four alkaloids, along with one known cycloheptenone oxide derivative, were isolated from the whole plants of Taraxacum mongolicum Hand.-Mazz. Their structures were elucidated by UV, IR, HR-ESI-MS, 1D and 2D NMR spectroscopy, ECD spectroscopy, or X-ray diffraction analysis. Notably, benzobicyclic ketones have never been isolated from nature before. The 70% EtOH-H2O extract of T. mongolicum displayed a significant inhibitory activity (33%) against croton oil-induced mouse ear edema. The two cycloheptenone oxide derivatives exhibited anti-inflammatory activities at 10 µM and significantly reduced the nitric oxide (NO) and interleukin-6 (IL-6) levels in RAW 264.7 macrophages induced by lipopolysaccharide (LPS), with inhibitory rates of 26.4-64.4%.

Comprehensive analysis of transcriptomics and metabolomics to illustrate the underlying mechanism of helenalin against hepatic fibrosis.

This study aimed to investigate the protective mechanisms of helenalin on hepatic fibrosis. In brief, rats were intragastrically administrated with 50% CCl4 for 9 weeks to induce liver fibrosis, followed by treatment with various agents for 6 weeks. The effects of helenalin on hepatic injury were assessed by pathological examinations. The potential targets were predicted by the "Drug-Disease" bioinformatic analysis and then verified by multiple experiments. Moreover, the underlying mechanism was investigated by transcriptomics and metabolomics as a whole. The results showed that helenalin significantly alleviated hepatocyte necrosis and hepatic injury, as proved by the pathological examinations. Also, helenalin markedly attenuated hepatocyte apoptosis by regulating the expression of caspase-3 and Bcl-2 families. Besides, helenalin could significantly reduce collagen accumulation, as evidenced by the decreased contents of collagen, hyaluronic acid and laminin. Moreover, helenalin significantly down-regulated the phosphorylation of PI3K, Akt, FAK, mTOR and P70S6K, and PTEN protein expression, suggesting that helenalin inhibited the PI3K/Akt signaling cascade. Meanwhile, helenalin inhibited the NF-κB signaling pathway by reducing the phosphorylation of IκBα, NF-κB p65 and IKKα/ß, alleviating inflammation response. Interestingly, the analysis of transcriptomics and metabolomics indicated that helenalin inhibited the glycerophospholipid metabolism pathway by down-regulating the target genes (CHKA, ETNPPL, LYPLA1, PCYT2, PLD4 and PNPLA6), ultimately ameliorating hepatocyte damage. In conclusion, helenalin ameliorates hepatic fibrosis by regulating the PI3K/Akt and NF-κB signaling pathways and the glycerophospholipid metabolism pathway.