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.

Phosphine-Catalyzed Synthesis and Cytotoxic Evaluation of Michael Adducts of the Sesquiterpene Lactone Arglabin.

A general method for chemo- and diastereoselective modification of anticancer natural product arglabin with nitrogen- and carbon-centered pronucleophiles under the influence of nucleophilic phosphine catalysts was developed. The locked s-cis-geometry of α-methylene-γ-butyrolactone moiety of arglabin favors for the additional stabilization of the zwitterionic intermediate by electrostatic interaction between phosphonium and enolate oxygen centers, leading to the unprecedentedly high efficiency of the phosphine-catalyzed Michael additions to this sesquiterpene lactone. Using n-Bu3P as the catalyst, pyrazole, phthalimide, 2-oxazolidinone, 4-quinazolinone, uracil, thymine, cytosine, and adenine adducts of arglabin were obtained. The n-Bu3P-catalyzed reaction of arglabin with active methylene compounds resulted in the predominant formation of bisadducts bearing a new quaternary carbon center. All synthesized Michael adducts and previously obtained phosphorylated arglabin derivatives were evaluated in vitro against eleven cancer and two normal cell lines, and the results were compared to those of natural arglabin and its dimethylamino hydrochloride salt currently used as anticancer drugs. 2-Oxazolidinone, uracil, diethyl malonate, dibenzyl phosphonate, and diethyl cyanomethylphosphonate derivatives of arglabin exhibited more potent antiproliferative activity towards several cancer cell lines and lower cytotoxicity towards normal cell lines in comparison to the reference compounds, indicating the feasibility of the developed methodology for the design of novel anticancer drugs with better therapeutic potential.

Synthesis and antihepatoma activity of guaianolide dimers derived from lavandiolide I.

Guaianolide dimers represent a unique class of natural products with anticancer activities, but their low content in plants has limited in-depth pharmacological studies. Lavandiolide I is a guaianolide dimer isolated from Artemisia species, and had been synthesized on a ten-gram scale in four steps with 60 % overall yield, which showed potent antihepatoma activity on the HepG2, Huh7, and SK-Hep-1 cell lines with IC50 values of 12.1, 18.4, and 17.6 µM, respectively. To explore more active dimers, 33 lavandiolide I derivatives were designed, synthesized, and evaluated for their inhibitory activity on human hepatoma cell lines. Among them, 10 derivatives were more active than lavandiolide I and sorafenib on the three cell lines. The primary structure-activity relationship concluded that the introduction of aldehyde, ester, azide, amide, carbamate and urea functional groups at C-14' of the guaianolide dimer significantly enhanced the antihepatoma activity. Among these compounds, derivatives 25, 27, and 33 enhanced antihepatoma activity more than 1.2-5.8 folds than that of lavandiolide I, and demonstrated low toxicity to the human liver cell lines (THLE-2) and good safety profiles with selective index ranging from 1.3 to 3.4, while lavandiolide I was more toxic to THLE-2 cells. This work provides new insights into enhancing the antihepatoma efficacy and reducing the toxicity of sesquiterpenoid dimers.

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.

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.

A Review on Torilis japonica: Ethnomedicinal, Phytochemical, and Biological Features.

The present study was aimed at comprehensive overviewing a phytochemically and biologically important species namely Torilis japonica (Apiaceae family). Treatment of dysentery, fever, haemorrhoids, spasm, uterine tumors, lymphadenitis, rheumatism, impotence, infertility, women's diseases, and chronic diarrhea are reported as the main folk medicinal applications of the T. japonica fruits. So far, the plant is phytochemically characterized for its diverse terpene derivatives, predominantly sesquiterpenes. The plant's fruit is a rich source of torlin, a guaiane-type sesquiterpene, possessing various potent bioactivities. To date, anticancer, anti-inflammatory, antimicrobial, antioxidant, skin photoaging activities of the plant extracts and its constituents have been evaluated. Further investigation of the plant, specifically bioassay-guided isolation and identification of its major bioactive constituents can lead to discover potential phytopharmaceutical candidates.

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.

Asymmetric Total Synthesis of (-)-Phaeocaulisin A.

The therapeutic properties of Curcuma (ginger and turmeric's family) have long been known in traditional medicine. However, only recently have guaiane-type sesquiterpenes extracted from Curcuma phaeocaulis been submitted to biological testing, and their enhanced bioactivity was highlighted. Among these compounds, phaeocaulisin A has shown remarkable anti-inflammatory and anticancer activity, which appears to be tied to the unique bridged acetal moiety embedded in its tetracyclic framework. Prompted by the promising biological profile of phaeocaulisin A and by the absence of a synthetic route for its provision, we have implemented the first enantioselective total synthesis of phaeocaulisin A in 17 steps with 2% overall yield. Our route design builds on the identification of an enantioenriched lactone intermediate, tailored with both a ketone moiety and a conjugated alkene system. Taking advantage of the umpolung carbonyl-olefin coupling reactivity enabled by the archetypal single-electron transfer (SET) reductant samarium diiodide (SmI2), the lactone intermediate was submitted to two sequential SmI2-mediated cyclizations to stereoselectively construct the polycyclic core of the natural product. Crucially, by exploiting the innate inner-sphere nature of carbonyl reduction using SmI2, we have used a steric blocking strategy to render sites SET-unreceptive and thus achieve chemoselective reduction in a complex substrate. Our asymmetric route enabled elucidation of the naturally occurring isomer of phaeocaulisin A and provides a synthetic platform to access other guaiane-type sesquiterpenes from C. phaeocaulis─as well as their synthetic derivatives─for medicinal chemistry and drug design.

Guaiane-type sesquiterpenes from Curcumawenyujin.

Eight undescribed sesquiterpenes including seven guaianes and one pseudoguaiane which were named as wenyujinols A-H, along with ten known guaianes, were isolated from rhizomes of Curcuma wenyujin Y. H. Chen et C. Ling. The structures of wenyujinols A-H were elucidated by 1D and 2D nuclear magnetic resonance (NMR) data, high resolution mass spectrum (HRMS), electronic circular dichroism (ECD) spectra, and X-ray single crystallographic analysis. All of the isolated compounds were evaluated for antioxidant activity via activation of the Nrf2-ARE pathway in human embryonic kidney (HEK) 293 cells, for inhibitory effects on NO production in RAW 264.7 cells, and for cytotoxicity against three human cancer cell lines A549, HL60, and MCF7 in vitro. The results indicated that procurcumenol (50-200 µM) and 9-oxo-neoprocurcumenol (25-200 µM) exhibited antioxidant activity via activation of the Nrf2-ARE pathway in a dose-dependent manner.

Challenging Approach to the Development of Novel Estrogen Receptor Modulators Based on the Chemical Properties of Guaiazulene.

Tamoxifen, a therapeutic agent for breast cancer, has been associated with genetic polymorphisms in the metabolism of N,N-dialkylaminoethyl substituent, which plays an important role in the expression of selective estrogen receptor modulator (SERM) activity. To solve this problem, we developed a novel estrogen receptor (ER) modulator, Az-01, on the basis of the aromaticity, dipole moment, and isopropyl group of guaiazulene. Az-01 showed four-fold lower binding affinity for ER than E2 but had similar ER-binding affinity to that of 4-hydroxytamoxifen (4-HOtam). Unlike tamoxifen, Az-01 acted as a partial agonist with very weak estrogenic activity at high concentrations when used alone, and it showed potent anti-estrogenic activity in the presence of E2. The cell proliferation and inhibition activities of Az-01 were specific to ER-expressing MCF-7 cells, and no effect of Az-01 on other cell proliferation signals was observed. These findings are important for the development of new types of SERMs without the N,N-dialkylaminoethyl substituent as a privileged functional group for SERMs.

Liquid-Liquid Chromatography Separation of Guaiane-Type Sesquiterpene Lactones from Ferula penninervis Regel & Schmalh. and Evaluation of Their In Vitro Cytotoxic and Melanin Inhibitory Potential.

Ferula penninervis Regel & Schmalh. is a perennial plant used in Kazakh traditional folk medicine to treat epilepsy, neurosis, rheumatism, gastroduodenal ulcers, dyspepsia, wounds, abscesses or tumors. The aim of this work was to isolate series of sesquiterpene lactones from a crude methanolic root extract and investigate their in vitro cytotoxic potential against androgen-dependent prostate cancer LNCaP and epithelial prostate PNT2 cells, as well as to evaluate their melanin production inhibitory effects in murine melanoma B16F10 cells stimulated with α-melanocyte-stimulating hormone (αMSH). Two new (penninervin P and penninervin Q) and five known (olgin, laferin, olgoferin, oferin and daucoguainolactone F) guaiane-type sesquiterpene lactones were isolated with the use of a simple and fast liquid-liquid chromatography method. Olgin and laferin showed the most promising cytotoxic effects in LNCaP cells (IC50 of 31.03 and 23.26 µg/mL, respectively). Additionally, olgin, laferin, olgoferin, and oferin (10 µg/mL) potently impaired melanin release (40.67-65.48% of αMSH + cells) without influencing the viability of B16F10 cells. In summary, our findings might indicate that guaiane-type sesquiterpene lactones from F. penninervis could be regarded as promising candidates for further research in discovering new therapeutic agents with anti-prostate cancer and skin depigmentation properties.

Arglabin could target inflammasome-induced ARDS and cytokine storm associated with COVID-19.

Arglabin (l(R),10(S)-epoxy-5(S),5(S),7(S)-guaia-3(4),ll(13)-dien-6,12-olide), is a natural sesquiterpene γ-lactone which was first isolated from Artemisia glabella. The compound has been shown to possess anti-inflammatory activity through inhibition of the NLR Family pyrin domain-containing 3 (NLRP3) inflammasome and production of proinflammatory cytokines including interleukin (IL)-1ß and IL-18. A more hydrophilic derivative of the compound also exhibited antitumor activity in the breast, colon, ovarian, and lung cancer. Some other synthetic derivatives of the compound have also been synthesized with antitumor, cytotoxic, antibacterial, and antifungal activities. Since both NLRP3 inflammasome and cytokine storm are associated with the pathogenesis of COVID-19 and its lethality, compounds like arglabin might have therapeutic potential to attenuate the inflammasome-induced acute respiratory distress syndrome and/or the cytokine storm associated with COVID-19.

Chemical Composition and Anticholinesterase Activity of the Essential Oil of Leaves and Flowers from the Ecuadorian Plant Lepechinia paniculata (Kunth) Epling.

This work aimed to study the chemical composition, cholinesterase inhibitory activity, and enantiomeric analysis of the essential oil from the aerial parts (leaves and flowers) of the plant Lepechinia paniculata (Kunth) Epling from Ecuador. The essential oil (EO) was obtained through steam distillation. The chemical composition of the oil was evaluated by gas chromatography, coupled to mass spectrometry (GC-MS) and a flame ionization detector (GC-FID). The analyses led to the identification of 69 compounds in total, of which 40 were found in the leaves and 29 were found in the flowers of the plant. The major components found in the oil were 1,8-Cineole, ß-Pinene, δ-3-Carene, α-Pinene, (E)-Caryophyllene, Guaiol, and ß-Phellandrene. Flower essential oil showed interesting selective inhibitory activity against both enzymes AChE (28.2 ± 1.8 2 µg/mL) and BuChE (28.8 ± 1.5 µg/mL). By contrast, the EO of the leaves showed moderate mean inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), with IC50 values of 38.2 ± 2.9 µg/mL and 47.4 ± 2.3 µg/mL, respectively.

Artematrovirenins A-P, guaiane-type sesquiterpenoids with cytotoxicities against two hepatoma cell lines from Artemisia atrovirens.

Random screening revealed that the EtOH extract of Artemisia atrovirens showed significant cytotoxicity against two human hepatoma cell lines (HepG2 and Huh7) with the inhibitory ratio of 98.9% and 99.7% at the concentration of 100 µg/mL. Further bioactivity-guided isolation of active fraction led to 16 new guaiane-type sesquiterpenoids, artematrovirenins A-P (1-16). Their structures were elucidated by extensive spectroscopic data. The absolute stereochemistry of compounds 1 and 14 was determined by single-crystal X-ray diffraction analyses. Pharmacological evaluation suggested that five compounds (3, 5, 8, 10, and 15) exhibited cytotoxicity, compounds 3 and 5 displayed cytotoxicity against HepG2 cell line with an IC50 values of 8.0 and 16.0 µM, as well as against Huh7 cell line with values of 18.2 and 32.2 µM.

Design, synthesis and in vivo anticancer activity of novel parthenolide and micheliolide derivatives as NF-κB and STAT3 inhibitors.

Parthenolide and micheliolide have attracted great attention in anticancer research due to their unique activities. In this study, thirteen parthenolide derivatives and twenty-three micheliolide derivatives were synthesized. Most synthesized compounds showed higher cytotoxicity than parthenolide or micheliolide. The in vivo anticancer activity of several representative compounds was evaluated in mice. One micheliolide derivative, 9-oxomicheliolide (43), showed promising in vivo antitumor activity compared with clinical drugs cyclophosphamide or temozolomide. Compound 43 was particularly effective against glioblastoma, with its tumor inhibition rate in mice comparable to the drug temozolomide. The discovery of compound 43 also demonstrates the feasibility of developing anticancer micheliolide derivatives by modification at C-9 position. Anticancer mechanism studies revealed that 9-oxomicheliolide exhibited inhibition effect against NF-κB and STAT3 signaling pathways, as well as induction effects of cell apoptosis. It is postulated that 9-oxomicheliolide is likely to be a modulator of the immune system, which regulates the anticancer immune responses.

Dimeric guaianes from leaves of Xylopia vielana as snail inhibitors identified by high content screening.

The transcriptional repressor Snail trriggers epithelial-mesenchymal transition (EMT), the process allowing cancer cells with invasive and metastasis properties. In this study, we screened medicinal plants for the Snail inhibitory active components by high content screen (HCS) and found that the crude extract of Xylopia vielana leaves showed potential activity. Subsequently, bioassay-guided isolation of the extract of Xylopia vielana was performed to obtain twenty-four dimeric guaianes (1-24), including 16 new analogues (1-5, 8-11, 13-15, 17, 18, 21, and 22). Their structures were elucidated by the comprehensive application of multiple spectroscopic methods. Compounds 1, 11, 12, and 16 were initially identified as the active compounds. Wound healing assay, transwell migration assay and western blot experiments verified that compounds 1 and 12 inhibited the expression of Snail in a concentration-dependent manner, and compound 12 was verified as a potent tumor migration inhibitory agent. This work showed a practical strategy for the discovery of new Snail inhibitors from natural products and provided potential insights for dimeric guaianes as anticancer lead compounds specifically targeting Snail protein.

Chlorinated Guaiane-Type Sesquiterpene Lactones as Cytotoxic Agents against Human Tumor Cells.

Guaiane-type sesquiterpene lactones are naturally occurring compounds which have attracted attention due to their array of biological activities. In this study, chlorinated guaianolides 1-8, isolated from plants of the genus Centaurea, were evaluated against the human leukemia cell lines HL-60, U-937, a specific U-937 cell line that overexpresses the anti-apoptotic Bcl-2 protein and the human melanoma cell line SK-MEL-1. This established the relevant structure-growth inhibition relationships. Chlorohyssopifolins A (1), C (3) and D (4) and linichlorin A (6) were the most potent compounds in terms of inducing growth inhibition in the four cell lines. IC50 values were below 10 µM in all cases. Chlorohyssopifolins A (1) and D (4) and linichlorin A (6) were potent apoptotic inducers in human U-937 leukemia cells, as determined by fluorescent microscopy and flow cytometry, and their mechanism of action was associated with cytochrome c release, caspase activation and poly(ADP-ribose)polymerase cleavage. Overall this study shows that guaianolides induce cytotoxicity against human tumor cells and provides important insights into the cell death pathways that are involved.

Antitumor Effects and Tumor-specificity of Guaiazulene-3-Carboxylate Derivatives Against Oral Squamous Cell Carcinoma In Vitro.

AIM: The aim of this study was to investigate the antitumor potential of guaiazulene-3-carboxylate derivatives against oral malignant cells. MATERIALS AND METHODS: Twelve guaiazulene-3-carboxylate derivatives were synthesized by introduction of either with alkyl group [1-5], alkoxy group [6, 7], hydroxyl group [8, 9] or primary amine [10-12] at the end of sidechains. Tumor-specificity (TS) was calculated by the ratio of mean 50% cytotoxic concentration (CC50) against 3 human oral mesenchymal cell lines to that against 4 human oral squamous cell carcinoma (OSCC) cell lines. Potency-selectivity expression (PSE) was calculated by dividing TS value by CC50value against OSCC cell lines. Cell cycle analysis was performed by cell sorter. RESULTS: [6, 7] showed the highest TS and PSE values, and induced the accumulation of both subG1 and G2/M cell populations in HSC-2 OSCC cells. Quantitative structure-activity relationship analysis demonstrated that their tumor-specificity was correlated with chemical descriptors that explain the 3D shape, electric state and ionization potential. CONCLUSION: Alkoxyl guaiazulene-3-carboxylates [6, 7] can be potential candidates of lead compound for developing novel anticancer drugs.

Machine learning for target discovery in drug development.

The discovery of macromolecular targets for bioactive agents is currently a bottleneck for the informed design of chemical probes and drug leads. Typically, activity profiling against genetically manipulated cell lines or chemical proteomics is pursued to shed light on their biology and deconvolute drug-target networks. By taking advantage of the ever-growing wealth of publicly available bioactivity data, learning algorithms now provide an attractive means to generate statistically motivated research hypotheses and thereby prioritize biochemical screens. Here, we highlight recent successes in machine intelligence for target identification and discuss challenges and opportunities for drug discovery.

Assignment of the stereostructures of sesquiterpenoids from the roots of Daphne genkwa via quantum chemical calculations.

Five new guaiane-type sesquiterpenoids were obtained from the roots of Daphne genkwa. Their gross structures were established by extensive spectroscopic analyses. Attempts on the assignment of the relative configurations were unsuccessful when based on the NOESY correlations. Therefore, NMR chemical shift calculations based on the gauge independent atomic orbital (GIAO) method in combination with the statistical method DP4+ were employed to establish their relative configurations. Furthermore, the absolute configurations were determined by comparing the experimental and calculated electronic circular dichroism (ECD) using time-dependent density functional theory (TDDFT). The isolated compounds were screened for their cytotoxicity in vitro against two human hepatocellular carcinoma, HepG2 and Hep3B cell lines.