Chemical constituents of Ligularia alticola Worosch. leaves and their biological activities

Seven eremophilane-type sesquiterpenes (1–7), six cycloartane derivatives (8–13) and α-amyrin acetate (14) were isolated from the leaves of the far-eastern plant Ligularia alticola Worosch. (Family Asteraceae). (4S,5R,8S,10R)-8-Ethoxyeremophil-7(11)-en-12(8)-olide (1), 8α,11-epidioxy-8β-methoxyeremophil-6-ene (2) and 29-norcycloartan-3α-ol (8) have not been previously reported. Fukinone α-epoxide (3) was isolated for the first time from a natural source. The structures of all the compounds were established by the extensive analysis of their 1D and 2D NMR spectra and HR ESI mass spectrometry. The absolute stereochemistry of 1 was determined by comparison of theoretical and experimental ECD spectra with the application of B3LYP-TDDFT and B3LYP-GIAO calculations as well as by NMR spectroscopy. Compound 1 showed cytotoxic action against human cancer HL-60, Raji, and THP-1 cell lines (IC₅₀ 12.6, 6.0 and 6.9 μM, respectively). Compounds 2 and 4 demonstrated significant cytotoxic activities against HL-60 (IC₅₀ 2.8 and 5.8 μM, respectively) and Raji cells (IC₅₀ 2.9 and 4.2 μM, respectively). Compound 6 was cytotoxic against Raji cells (IC₅₀ 4.6 μM). None of tested compounds were cytotoxic against RAW 264.7 cells. Compounds 1 and 4–7 significantly decreased intracellular ROS levels, induced by endotoxic LPS from Escherichia coli in RAW 264.7 murine macrophages.     

Cytotoxic triterpene saponins from the stem bark of Kalopanax pictus

Three new compounds, 3β,6β,23-trihydroxyolean-12-en-28-oic acid 3-O-α-l-arabinopyranoside (1), kalopanaxsaponin L (2), and kalopanaxsaponin M (13), as well as eleven known compounds (3–12 and 14), were isolated from the stem bark of Kalopanax pictus. Their structures were determined on the basis of extentive spectroscopic analyses and acid hydrolysis. The cytotoxicity of the compounds was evaluated in three human carcinoma cell lines, including HL-60, HCT-116, and MCF-7. Compounds 1, 5–8, 10, and 11 exhibited significantly cytotoxic activity toward HL-60 cells, with IC₅₀ values ranging from 0.1 to 6.9 μM. Compounds 4–7 and 14 showed significant cytotoxicity against HCT-116 cells, with IC₅₀ values ranging from 0.4 to 9.2 μM. Remarkably, the cytotoxic activities of compounds 5–7 against HCT-116 cells were greater than that of the anticancer chemotherapy drug, mitoxantrone (IC₅₀ = 3.7 μM). Compounds 1, 3, 5, and 14 were cytotoxic toward MCF-7 cells with IC₅₀ values in a range of 7.4–14.5 μM.     

Dammarane-type saponins from the flower buds of Panax ginseng and their effects on human leukemia cells

Six dammarane-type saponins, including three new compounds, floralginsenosides Ta–Tc (1–3), and three known, floralginsenoside Td (4), ginsenoside F₁ (5), and ginsenoside F₅ (6), were isolated from the flower buds of Panax ginseng. Floralginsenoside Td (4) was first isolated from natural plant sources. Their structures were elucidated on the basis of extensive chemical and spectroscopic methods. Compounds 1, 5, and 6 showed cytotoxic activities towards the HL-60 human leukemia cell line with respective IC₅₀ values of 36.3, 23.2, and 62.4 μM. In addition, after the HL-60 cells were treated with these compounds, several apoptosis events, including chromatin condensation and increase in the population of sub-G1 hypodiploid cells, were observed.     

α-Pyrone derivatives with cytotoxic activities,from the endophytic fungus Phoma sp. YN02-P-3

Four new α-pyrone derivatives phomones C-F (1?4) together with four known compounds (5?8) were isolated from the endophytic fungus Phoma sp. YN02-P-3. Compound 1 is the first example of 6-α,β-unsaturated ester-2-pyrone dimers via intermolecular symmetrical [2 + 2] cycloaddition. The chemical structures of these compounds were determined from spectroscopic data (1D/2D NMR, MS and IR). The acetylated product (9) of 1 along with compounds 1–8 were then tested for their cytotoxicity against HL-60, PC-3 and HCT-116 cell lines. Compounds 2, 3, 5 and 9 with acetyl groups showed significant inhibitory activities against the three cell lines with IC₅₀ values in the range 0.52–9.85 μM. while compounds 1, 4 and 6–8 that possess no acetyl group showed no inhibitory activity (IC₅₀ > 50 μM), indicating that the acetyl group at 10- or 12- are essential for their cytotoxic activities. The structure-activity relationships of these phomones were also reported.     

Tirucallane triterpenoids from the stem bark of Araliopsis synopsis

Two new tirucallane triterpenoids, 21-methoxy-21,23-epoxy-tirucalla-7,24-dien-3α-ol (1) and 21-methoxy-21,23-epoxy-tirucalla-7,24-diene-1α,3α-diol (2), together with thirteen known compounds were isolated from the CH₂Cl₂ extract of the stem bark of Araliopsis synopsis. The structures of the compounds were determined by comprehensive analyses of their 1D and 2D NMR, mass spectral (EI and ESI) data and comparison with previously known analogs. Compounds 1–10 were tested against bacteria, fungi and plant pathogen oomycetes by the paper disk agar diffusion assay resulting in missing to low activities corresponding with MICs > 1 mg/mL. However, compounds 5–10 exhibited high cytotoxic activity against the human Caucasian prostate adenocarcinoma cell PC-3 line, with IC₅₀ 8.5–12.5 μM compared to the standard Doxorubicin with IC₅₀ = 0.9 μM, while compounds 1, 3 and 4 showed low activity.     

Three new chlorinated phenolic glycosides from Przewalskia tangutica

Three new chlorinated phenolic glycosides, namely przewatangosides A-C (1-3), along with one known compound, globosumoside A (4), were isolated from the whole plants of Przewalskia tangutica. Their structures were unequivocally determined by extensive spectroscopic analysis and chemical method. The cytotoxic activities of the isolated phenolic glycosides (1-4) were evaluated against the five human cancer cell lines A549, MCF-7, SMMC-7721, HepG2 and HL-60. Przewatangoside A (1) exhibited weak cytotoxicity against SMMC-7721 with the IC₅₀ value of 38.1 μM. All the tested compounds were inactive (IC₅₀ > 50 μM) to the normal human hepatocyte cell line (L02).     

Bioactive 2-pyrone metabolites from an endophytic Phomopsis asparagi SWUKJ5.2020 of Kadsura angustifolia

Five new 2-pyrone metabolites, phomaspyrones A–E (1–5) along with three known compounds, macommelin-8,9-diol (6), macommelin-9-ol (7), and macommelin (8), were isolated from the culture broth of an endophytic fungus Phomopsis asparagi SWUKJ5.2020 of medicinal plant Kadsura angustifolia by sequentially purification over silica gel, Sephadex LH-20 column chromatography and preparative HPLC. Their structures were elucidated on the basis of spectroscopic analysis, including two-dimensional (2D) NMR and HRMS (ESI-TOF) data. Among them, compounds 3–5 exhibited notable cytotoxicity against HL-60 and K562 cells with IC₅₀ values of below 10 μg/mL better than those of the other isolated metabolites (IC₅₀ = 10.6–26.6 μg/mL). The results showed that the keto or hemiketal functionality might play an important role in cytotoxic activity of this class of compounds.     

Four new triterpenoidal saponins from Ilex cornuta and their cytotoxic activities

Four new triterpenoidal saponins (1–4), oleanolic acid 3β-O-α-l-arabinopyranosyl-(1 → 2)-β-d-glucuronopyranoside-6-O-butyl ester (1), oleanolic acid 3β-O-[α-l-arabinopyranosyl-(1 → 2)-β-d-glucuronopyranoside-6-O-butyl ester]-28-O-β-d-glucopyranoside (2), 19α-hydroxy oleanolic acid 3β-O-β-d-glucuronopyranoside-6-O-methyl ester (3), and 19α-hydroxy urs-12-en-28-oic acid 3β-O-α-l-arabinopyranosyl-(1 → 2)-β-d-glucuronopyranoside-6-O-methyl ester (4) were isolated from the roots of Ilex cornuta. Their structures were determined by means of extensive spectroscopic analyses (IR, ESIMS, HRESIMS, 1D and 2D NMR). Compounds 1–9 were tested for their cytotoxic activities by MTT assay, and 1, 3, 5 and 6 showed moderate cytotoxic activities against HeLa, SMMC-7721, and HL-60 human tumor cell lines.     

Triterpene compounds isolated from Acer mandshuricum and their anti-inflammatory activity

In our preliminary screening study on the anti-inflammatory activity, a new triterpene compound, aceranol acetate (1), was isolated along with five known compounds: β-amyrin acetate (2); glutinol acetate (3); friedelin (4); glutinol (5); (3β)-d-glucopyranoside-stigmast-5-en-3-yl (6), from the stems and leaves of Acer mandshuricum. The structure of the new triterpene was determined to be 5α,6α-epidioxy-5β,6β-epoxy-9,13-dimethyl-25,26-dinoroleanan-3β-ol acetate by spectroscopic studies. Compounds 2–6 were isolated from this plant for the first. Five triterpene compounds (1–5) showed significant cytotoxic activity with GI₅₀ in the range of 11.1–17.9 μM, whereas steroid compound (6) exhibited moderate activity against four human cancer cell lines (HL-60, SK-OV-3, A549, and HT-29). Furthermore, the anti-inflammatory effects of compounds 1–6 in the non-cytotoxic concentrations (1–100 nM) were evaluated for the inhibitory activity of TNF-α secretion in the lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophage cell line. Among the compounds tested, compound 2 showed the strongest anti-inflammatory activity with the inhibition rate up to 38.40% at the concentration of 100 nM, whereas other five compounds (2–6) exhibited moderate activity.     

The application of Heck reaction in the synthesis of guaianolide sesquiterpene lactones derivatives selectively inhibiting resistant acute leukemic cells

A series of guaianolide-type sesquiterpene lactones derivatives with arylation of α-methylene-γ-lactone moiety was synthesized using Heck reactions, and was evaluated for their activities against acute myelogenous leukemia (AML) cell line HL-60 and doxorubicin-resistant cell line HL-60/A. Although all compounds were significantly less active against HL-60 than the parent molecules, surprisingly, compounds 3a, 4c–4e, 5e, and 8d exhibited high potency against doxorubicin-resistant cell line HL-60/A (IC₅₀ = 6.2–19 μM), and their activities against HL-60/A were comparable to that of their parent molecules. In view of their novel activities against HL-60/A, compound 5e with inhibitory activity against HL-60/A (IC₅₀ = 6.2 ± 0.5 μM) was selected for study its preliminary mechanism. The result reveals that compound 5e can obviously induce apoptosis.     

Xanthones from the stem bark of Garcinia bracteata with growth inhibitory effects against HL-60 cells

Five xanthones, 1,4,5,6-tetrahydroxyxanthone (1) and bracteaxanthones III–VI (2–5) together with twenty-six known compounds (6–31), were isolated from the ethanol extract of the stem bark of Garcinia bracteata. Their structures were elucidated via spectroscopic analyses. Growth inhibitory activities of these compounds against the human leukaemic HL-60 cell line were measured in vitro. Compounds 7, 11, and 29 exhibited moderate activities with GI₅₀ values of 2.8, 3.4, and 3.1 μM, respectively, and a preliminary structure–activity relationship is discussed.     

Triterpenoid saponins and C-glycosyl flavones from stem bark of Erythrina abyssinica Lam and their cytotoxic effects.

Six new compounds including two oleanane-type triterpenoid saponins (1, 2) and four C-glycosyl flavones (3–6), along with a known saponin (7), three di-C-glycosyl flavones (8–10) and a glycosyl auronol (11), were isolated from the stem bark of Erythrina abyssinica Lam. The structures of the new compounds, identified as 3-O-[α-l-rhamnopyranosyl-(1 → 2)-β-d-galactopyranosyl-(1 → 2)-β-d-glucuronopyranosyl]-22-O-β-d-glucopyranosyl sophoradiol (1), 3-O-[α-l-rhamnopyranosyl-(1 → 2)-β-d-glucopyranosyl-(1 → 2)-β-d-glucuronopyranosyl]-22-O-β-d-glucopyranosyl sophoradiol (2), 6-C-β-glucopyranosyl-8-C-β-quinovopyranosyl apigenin (3), 6-C-β-quinovopyranosyl-8-C-β-glucopyranosyl apigenin (4), 8-C-[6″-O-α-l-rhamnopyranosyl-(1‴ → 6″)]-β-glucopyranosyl 7,4′-dihydroxyflavone (5) and 8-C-[6″-O-β-d-xylopyranosyl-(1‴ → 6″)]-β-glucopyranosyl 7,4′-dihydroxyflavone (6), were determined by comprehensive spectroscopic analysis, including 1D and 2D NMR techniques, mass spectrometry and acid hydrolysis. These new compounds together with the known saponins 7 were evaluated for their cytotoxic activity against MCF-7 (estrogen dependent) and MDA-MB-231 (estrogen independent) cell lines. The new saponin 2 exhibited the highest cytotoxic activity among tested compounds, exerting a selective inhibitory effect against the proliferation of MCF-7 cells, with lower IC₅₀ value (12.90 μM) than that of the positive control, resveratrol (13.91 μM). Structure–activity relationship of these compounds is also discussed.     

Two new eudesmanolides from Inula racemosa and their bioactivities

Two new eudesmane-type sesquiterpene lactones, 1-one-4-epi-alantolactone (1) and 4α,13-dihydroxy-5,7(11)-eudesmadien-12,8-olide (2), were isolated from the roots of Inula racemosa, together with six known compounds (3–8). The cytotoxic activities against five human cancer cell lines had been tested and compounds 3, 6, 7 and 8 exhibited moderate cytotoxic activities. Compounds 4 and 8 showed potent in vitro activities against the release of β-glucuronidase in rat polymorphonuclear leukocytes (PMNs) induced by platelet-activating factor (PAF), with the inhibitory ratios 65.4% (P < 0.01) and 80.5% (P < 0.001), at concentration of 10 μM, respectively.     

Synthesis and DNA cleavage activity of 2-hydrazinyl-1,4,5,6-tetrahydropyrimidine containing hydroxy group

2-Hydrazinyl-1,4,5,6-tetrahydropyrimidin-5-ol dihydrochloride 2, as well as 2-hydrazinyl-4,5-dihydro-1H-imidazole dihydrochloride 1, was synthesized as metal-free DNA cleaving agent. Agarose gel electrophoresis was used to assess the plasmid pUC 19 DNA cleavage activities in the presence of 1 and 2. DNA cleavage efficiency of 2 exhibits remarkable increases compared with its corresponding non-hydroxy compound 1. Kinetic data of DNA cleavage promoted by 2 fit to the Michaelis–Menten-type equation with k_max of 0.0378 ± 0.0013 h^?1 giving 10⁶-fold rate acceleration over uncatalyzed DNA. The acceleration is driven by the spatial proximity of the nucleophilic hydroxy group and the electrophilic activation for the phosphodiester by the ammonium and/or guanidinium groups. In vitro cytotoxic activities toward Hela cells and human leukemia HL-60 cells were also examined, and 2 exhibits stronger cytotoxic activities than 1.     

Two novel neo-clerodane diterpenoids from Scutellaria barbata

Two novel neo-clerodane diterpenoids, barbatellarines A (1) and B (2), were isolated from the whole plants of Scutellaria barbata, along with the known compound scutebarbatine F (3). The chemical structures and relative stereochemistry of the isolated compounds were established by NMR (1D and 2D) and mass spectroscopic analyses. Compounds 2 and 3 were evaluated for in vitro cytotoxic activity against the HL-60 (human leukemia), MCF7 (human breast cancer), and LLC (Lewis lung carcinoma) cancer cell lines. Compound 2 exhibited weak cytotoxic activity against HL-60 cells, with an IC₅₀ value of 41.4 μΜ.     

Syntheses of cytotoxic novel arctigenin derivatives bearing halogen and alkyl groups on aromatic rings

The new lignano-9,9′-lactones (α,β-dibenzyl-γ-butyrolactone lignans), which showed the higher cytotoxicity than arctigenin, were synthesized. The well-known cytotoxic arctigenin showed activity against HL-60 cells (EC₅₀ = 12 μM), however, it was inactive against HeLa cells (EC₅₀ > 100 μM). The synthesized (3,4-dichloro, 2′-butoxy)-derivative 55 and (3,4-dichloro, 4′-butyl)-derivative 66 bearing the lignano-9,9′-lactone structures showed the EC₅₀ values of 10 μM and 9.4 μM against HL-60 cells, respectively. Against HeLa cells, the EC₅₀ value of the derivative 66 was 27 μM. By comparing the activities with the corresponding 9,9′-epoxy structure (tetrahydrofuran compounds), the importance of the lactone structure of 55 and 66 for the higher activities was shown. The substituents on the aromatic ring of the lignano-9,9′-lactones affected the cytotoxicity level, observing more than 10-fold difference.     

Bioactive lignans from Zanthoxylum planispinum with cytotoxic potential

Zanthoxylum planispinum Sieb. et Zucc is used in traditional oriental medicinal for preventing toothache, treating colds and expelling roundworms. Its fruit is widely used as a spice in cuisines in East Asian countries. Two previously unreported dilignans with a rare α,β-unsaturated ketone group, bizanthplanispine A and B (1–2), together with two known dilignans, zanthpodocarpins A and B (3–4), and four known lignans, fargesin (5), planispine A (6), pinoresinol-di-3,3-dimethylallyl (7), and eudesmin (8), were isolated from the roots of Z. planispinum. The structures of these compounds were elucidated by extensive NMR and MS analysis. The cytotoxic activity of the isolated compounds was evaluated on three human cancer cell lines. Compounds 1–4 significantly reduced the proliferation of Hela with IC₅₀ values ranging from 15.00 to 26.44 μg/mL. Furthermore, compound 6 showed the strongest inhibitory effect on the growth of HL-60 and PC-3 with IC₅₀ values of 4.90 and 23.45 μg/mL, respectively. These data suggested that compounds 1–4, and 6 from Z. planispinum have potential as anticancer substances.     

Two polymethoxylated flavonoids with antioxidant activities and a rearranged clerodane diterpenoid from the leaf exudates of Microglossa pyrifolia

Three novel compounds; two polymethoxylated flavonoids, 5,7,4′-trihydroxy-3,8,3′,5′-tetramethoxyflavone (1), 5,7,3′-trihydroxy-3,8,4′,5′-trimethoxyflavone (2), and a clerodane diterpenoid; 8-acetoxyisochiliolide lactone (3) were characterized from the leaf exudates of Microglossa pyrifolia. In addition, three known polymethoxylated flavonoids including; 5,7,4′-trihydroxy-3,8,3′-trimethoxyflavone (4), 5,3′4′-trihydroxy-3,7,8-trimethoxyflavone (5), 5,3′4′-trihydroxy-7-methoxyflavanone (6) and a clerodane diterpenoid; 7,8-epoxyisocholiolide lactone (7) were identified. Their structures were determined on the basis of spectroscopic evidence. All the compounds did not exhibit antiplasmodial and antimicrobial activities at 47.6 μg/mL and were not cytotoxic at 5 μg/mL. Compound 6 exhibited modest antileishmanial activity with IC₅₀ value of 13.13 μg/mL with 5 and 7 showing activities with IC₅₀ values of 31.13 and 38.00 μg/mL, respectively, therefore inactive. The flavonoids (quercetin derivatives, 4 and 5) showed similar antioxidant activities, using 2,2-diphenylpicrylhydrazyl (DPPH) assay, with IC₅₀ values of 6.2 ± 0.3 μg/mL for 4 (17.3 μM) and 5 (17.8 μM) respectively. These activities were comparable to that of the standard quercetin (IC₅₀ value of 6.0 ± 0.2 μg/mL (19.9 μM)), irrespective of methylation of the characteristic hydroxyl groups expected to be responsible for activity and additional substitution at C-8 in ring A of the flavonoid ring. These studies revealed that the presence of an hydroxyl group at C-4′ positions and oxygenation at C-3 in flavone skeleton, appears to be necessary for good antioxidant activities as encountered in compounds 1, 4 and 5. Substantial reduction in antioxidant activity was shown by methoxylation of the 4′-OH as observed in compound 2 with an IC₅₀ value of 8.79 ± 0.3 μg/mL (24.4 μM).     

Scutelinquanines A–C,three new cytotoxic neo-clerodane diterpenoid from Scutellaria barbata

Three new neo-clerodane diterpenoids, named scutelinquanines A–C (1–3), were isolated from the whole plant of Scutellaria barbata. Their structures were established on the basis of detailed spectroscopic analyses. In vitro, the isolated three new compounds showed significant cytotoxic activities against three human cancer lines (HONE-1 nasopharyngeal, KB oral epidermoid carcinoma, and HT29 colorectal carcinoma cells), and gave IC₅₀ values in the range 2.7–6.7 μM.     

Pencitrin and pencitrinol,two new citrinin derivatives from an endophytic fungus Penicillium citrinum salicorn 46

Two new citrinin derivatives, pencitrin (1) and pencitrinol (2), and a known compound citrinin (3), together with its two known dimers, penicitrinone A (4), penicitrinone E (5), were isolated from an endophytic fungus P. citrinum 46 derived from Salicornia herbacea Torr. by adding CuCl₂ into fermentation medium. The structures of these compounds were elucidated by detailed spectroscopic analysis, and the absolute configurations of 1, 4, and 5 were determined by comparison of quantum chemical time-dependent density functional theory (TDDFT) calculated and electronic circular dichroism (ECD) spectra. Compound 1 exhibited potent cytotoxic activities towards A549 human lung cancer cells and HepG2 human liver cancer cells with IC₅₀ values of 23.73 ± 3.61 and 35.73 ± 2.15 μM, respectively, whereas compound 5 showed moderate cytotoxic activities towards A549 and HepG2 cancer cells with IC₅₀ values of 40.47 ± 4.52 and 53.57 ± 3.24 μM, respectively. The results from the current research highlighted the effectiveness and usefulness of the pipeline to discover novel bioactive fungal secondary metabolites by modification of the culture media.