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).     

Synthesis and in vitro cytotoxic evaluation of new 1H-benzo[d]imidazole derivatives of dehydroabietic acid

A series of new 1H-benzo[d]imidazole derivatives of dehydroabietic acid were designed and synthesized as potent antitumor agents. Structures of the target molecules were characterized using MS, IR, ¹H NMR, ¹³C NMR and elemental analyses. In the in vitro cytotoxic assay, most compounds showed significant cytotoxic activities against two hepatocarcinoma cells (SMMC-7721 and HepG2) and reduced cytotoxicity against noncancerous human hepatocyte (LO2). Among them, compound 7b exhibited the best cytotoxicity against SMMC-7721 cells (IC₅₀: 0.36 ± 0.13 μM), while 7e was most potent to HepG2 cells (IC₅₀: 0.12 ± 0.03 μM). The cell cycle analysis indicated that compound 7b caused cell cycle arrest of SMMC-7721 cells at G2/M phase. Further, compound 7b also induced the apoptosis of SMMC-7721 cells in Annexin V-APC/7-AAD binding assay.     

Platachromone A–D: Cytotoxic 2-styrylchromones from the bark of Platanus × acerifolia (Aiton) Willd.

Four novel 2-styrylchromones, 4′,5,7-trihydroxy-6-isopentene-2-styrylchromone (1), 4′,5,7-trihydroxy-8-isopentene-2-styrylchromone (2), 4′,5,7-trihydroxy-6-(2-hydroxy-3-methylbut-3-enyl)-2-styrylchromone (3) and 4′,5,7-trihydroxy-8-(2-hydroxy-3-methylbut-3-enyl)-2-styrylchromone (4), were isolated from shed bark of Platanus × acerifolia (Aiton) Willd., as well as four known compounds, 4′,5,7-trihydroxy-2-styrylchromone (5), scutellarein (6), 4′,5,7-trihydroxy-6-prenylflavone (7), and 4′,5,7-trihydroxy-8-prenylflavone (8). The structures of compounds 1–4 were established by direct interpretation of their spectral data, mainly high resolution electrospray ionization mass spectrometry (HR-ESI-MS), 1D and 2D NMR (¹H–¹H COSY, HSQC and HMBC). The cytotoxicity of the compounds 1–8 was evaluated in four human carcinoma cell lines, including HepG2, SMMC-7721, MDA-MB-231, and KB. Compounds 1–4 exhibited significantly cytotoxic activity toward HepG2 and KB cells, with IC₅₀ values ranging from 3.0 to 9.7 μM.     

Chemical constituents from Lonicera japonica flower buds and their anti-hepatoma and anti-HBV activities

Three new naturally occurring monoterpenoids, japopenoid A (1), japopenoid B (23) japopenoid C (24), and one new caffeoylquinic acid derivative (28), together with thirty-one known compounds (2–22, 25–27, 29–35), were isolated and identified from the flower buds of Lonicera japonica Thunb. Their structures were determined by extensive 1D and 2D NMR spectroscopic methods, high-resolution mass spectrometry, and the absolute configurations of 1, 23, 24 were determined by comparison of their electronic circular dichroism (ECD) spectrum with literature and theoretical calculation. Structurally, compound 1 is a monoterpenoid featured with an unusual tricyclic skeleton. All compounds (1–35) were evaluated for their cytotoxicities against human liver cancer cell lines (HepG 2 and SMMC-7721). Compound 12 exhibited the most potent activity with IC₅₀ values of 26.54 ± 1.95 and 8.72 ± 1.57 μg/ml against HepG 2 and SMMC-7721, and the IC₅₀ values of compound 13 were 26.54 ± 1.95 and 12.35 ± 1.43 μg/ml, respectively. Western blot results further proved that compound 13 induces hepatoma cell apoptosis via the intrinsic apoptosis pathway. In addition, most terpenoids showed inhibitory activity against HBsAg and HBeAg secretion, and HBV DNA replication. In particular, 25 μg/mlof compound 11 inhibits HBsAg and HBeAg secretion, and HBV DNA replication by 39.39 ± 5.25, 15.64 ± 1.25, and 16.13 ± 4.10% compared to the control (p < 0.05). These results indicated that L. japonica flower buds could be served as functional food for anti-hepatoma and anti-HBV activities.     

Cytotoxic and anti-inflammatory effects of lignans and diterpenes from Cupressus macrocarpa

Cupressus macrocarpa is a windbreak tree and is reported to have various cytotoxic effects. A natural product study on the leaves of C. macrocarpa has yielded ten secondary metabolites, including three new diterpenoids (1–3), four known diterpenoids (4–7), and three known lignans (8–10). The structures of all isolated compounds were elucidated via the interpretation of spectroscopic methods, especially 2D NMR and mass analyses. In the cytotoxic assays, compounds 1–3 and 7–10 showed inhibition effect against HepG2, MDA-MB-231, and A549 cells with IC₅₀ values ranging from 0.004 to 19.9 μg/mL. Moreover, the anti-inflammatory assays revealed that (−)-matairesinol (8) had significant inhibitory activities on superoxide anion generation (IC₅₀ = 2.7 ± 0.3 μM) and elastase release (IC₅₀ = 6.6 ± 0.7 μM).     

Three cytotoxic Annonaceous acetogenins from the seeds of Annona squamosa

Three new Annonaceous acetogenins, squamocin-IV (1), squamocin-V (2) and squamoxinone-E (3), together with seven other known Annonaceous acetogenins (4–10) were isolated from the seeds of Annona squamosa. The structures of all of the isolates were established and characterized through spectral and chemical methods. The new Annonaceous acetogenins 1–3 were evaluated for their cytotoxicity against the Hep-G2, SMMC-7721, BEL-7402, BGC-803 and H460 human cancer cell lines. Compound 3 exhibited the best cytotoxic activity, with IC₅₀ values of 0.103, 0.687, 4.19, 0.43 and 6.56 μg/mL, respectively for the cell lines above; meanwhile, Compound 1 showed selective cytotoxic activity against H460, with an IC₅₀ value of 0.049 μg/mL. The first mono-ACG (2) composed of 38 carbons was discovered.     

New cassane diterpenes from the fruits of Caesalpinia mimosoides Lam.

Six new cassane diterpenes, caesmimosins A-F (1–6) were isolated from the fruits of Caesalpinia mimosoides Lam. Their structures were identified by 1D and 2D NMR spectral data. Compounds 1–6 were evaluated for their cytotoxicity on HL-60, SMMC-7721, A-549, MCF-7 and SW-480 human cancer cell lines, they did not show inhibitory cytotoxic activities at a concentration of 40 μM against the five cell lines.     

Cytotoxicity of a naturally occurring furoquinoline alkaloid and four acridone alkaloids towards multi-factorial drug-resistant cancer cells

IntroductionChemotherapy is one of the preferred mode of treatment of malignancies, but is complicated by the expression of diverse resistance mechanisms of cancer cells.MethodsIn the present study, we investigated the cytotoxicity of five alkaloids including a furoquinoline montrofoline (1) and four acridones namely 1-hydroxy-4-methoxy-10-methylacridone (2), norevoxanthine (3), evoxanthine (4), 1,3-dimethoxy-10-methylacridone (5) against 9 drug-sensitive and multidrug-resistant (MDR) cancer cell lines. The resazurin reduction assay was used to evaluate the cytotoxicity of these compounds, whilst caspase-Glo assay was used to detect caspase activation. Cell cycle, mitochondrial membrane potential (MMP) and levels of reactive oxygen species (ROS) were all analyzed via flow cytometry.ResultsFuroquinoline 1 as well as the acridone alkaloids 2–5 displayed cytotoxic effects with IC₅₀ values below 138 µM on all the 9 tested cancer cell lines. The IC₅₀ values ranged from 41.56 µM (towards hepatocarinoma HepG2 cells) to 90.66 µM [towards colon carcinoma HCT116 (p53^−/−) cells] for 1, from 6.78 µM [towards HCT116 (p53^−/−) cells) to 106.47 µM [towards breast adenocarcinoma MDA-MB-231-pcDNA cells] for 2, from 5.72 µM (towards gliobastoma U87MG.ΔEGFR cells) to 137.62 µM (towards leukemia CCRF-CEM cells] for 3, from 6.11 µM [towards HCT116 (p53^+/+) cells] to 80.99 µM (towards HepG2 cells] for 4, from 3.38 µM (towards MDA-MB-231-BCRP cells) to 58.10 µM (towards leukemia CEM/ADR5000 cells] for 5 and from 0.20 µM (against CCRF-CEM cells) to 195.12 µM (against CEM/ADR5000 cells) for doxorubicin. Acridone alkaloid 5 induced apoptosis in CCRF-CEM leukemia cells, mediated by increased ROS production.ConclusionsThe five tested alkaloids and mostly acridone 5 are potential cytotoxic natural products that deserve more investigations to develop novel cytotoxic compounds against multifactorial drug-resistant cancers.     

Two new strophanthidol cardenolides from the seeds of Antiaris toxicaria

Two new strophanthidol cardenolides, toxicarioside N (1) and toxicarioside O (2), together with three known ones, were isolated from the seeds of Antiaris toxicaria. The structures of the new compounds were identified as strophanthidol-3-O-β-d-glucopyranosyl-(1 → 4)-6-deoxy-β-d-allopyranoside (1) and strophanthidol-3-O-β-d-glucopyranoside (2), respectively. The cytotoxic test showed that compounds 1 and 2 exhibited significant cytotoxicity against SMMC-7721 and K562.     

C21 steroidal glycosides with cytotoxic activities from Cynanchum otophyllum

Eight new C21 steroidal glycosides, namely cynanotins A–H (1–8), together with fifteen known analogues, were isolated from the roots of Cynanchum otophyllum. Their structures were elucidated by spectroscopic analysis and chemical methods. In this study, all of isolates were tested for their vitro inhibitory activities against five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7 and SW480). Compounds 3–15 showed moderate cytotoxic activities against HL-60 cell lines with IC₅₀ values ranging from 11.4 to 37.9?µM. Compounds 5, 9, and 10 showed marked or moderate cytotoxic activities against five human tumor cell lines with IC₅₀ values ranging from 11.4 to 36.7?µM. Compound 11 displayed moderate cytotoxic activities against HL-60, SMMC-7721, MCF-7 and SW480 cell lines with IC₅₀ values of 12.2–30.8?µM. Compared to the positive control (IC₅₀: 35.0?µM), compounds 5, 9–11 exhibited more potential inhibitory activity against MCF-7 cells (IC₅₀: 16.1–25.6?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.     

Design,synthesis, and docking studies of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors

Four series of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (12a–e, 13a–f, 14a–f and 15a–i) were designed, synthesized and evaluated for the IC₅₀ values against three cancer cell lines (A549, PC-3 and MCF-7) and c-Met kinase. Five selected compounds (13b, 15b, 15d, 15e and 15f) were further evaluated for the activity against HepG2 and Hela cell lines. Eighteen of the compounds showed excellent cytotoxicity activity and selectivity with the IC₅₀ valuables in single-digit μM to nanomole range. Seven of them are equal to more active than positive control Foretinib against one or more cell lines. The most promising compound 15f showed superior activity to Foretinib, with the IC₅₀ values of 1.04 ± 0.11 μM, 0.02 ± 0.01 μM and 9.11 ± 0.55 μM against A549, PC-3 and MCF-7 cell lines, which were 0.62 to 19.5 times more active than Foretinib (IC₅₀ values: 0.64 ± 0.26 μM, 0.39 ± 0.11 μM, 9.47 ± 0.22 μM), respectively. Structure–activity relationships (SARs) and docking studies indicated that replacement of quinoline nucleus of the previous active compounds with 1H-pyrrolo[2,3-b]pyridine moiety maintained even improved the potent cytotoxic activity. The results suggested that the introduction of fluoro atoms to the aminophenoxy part of target compounds or the phenyl group of pyrimidine substituted on C-4 position was benefit for the activity.     

Synthesis,toxicity and antitumor activity of cobalt carbonyl complexes targeting hepatocellular carcinoma

Based on our previous research, a series of targeting hepatocellular carcinoma complexes, [R-Glycyrrhetinic acid-CH₂C₂H-[Co₂(CO)₆] (R = H, 1; R = NSAIDs-COOH, 2–4; R = Aromatic acid, 5–7; R = Amino acid, 8–10), were synthesized. The test showed they are slow CO releasers. Using HeLa, A549, HT-29, SMMC7721 and HepG2 cells as models, their activities against tumor cell proliferation were firstly evaluated. The resulting data show all the complexes displayed a good anti-proliferation activity against the HepG2 and SMMC-7721 liver cancer cells, and their IC₅₀ values were in the range of 10.07–66.06 µM; compared with cis-platin (DDP), their activities were comparable or even better under the same condition. Among them, complexes 3, 4, 6 and 9 exhibited higher anti-proliferation activities against HepG2 and SMMC-7721 cell lines than the other cell lines. To confirm further these complexes have selectivity to the liver cells, the uptakes of complexes 3, 4, 6 and 9 by HepG2, HT-29, A549 and SMMC7721 cell lines were studied. The results show the cell uptake rates of the complexes by HepG2 cells and SMMC7721 cells were much greater than by other cells under the same condition. In following tests, the tested complexes displayed higher activities in inhibiting NF-kB, COX-2 and iNOS; and they induced HepG2 cells apoptosis by mitochondrial pathway, which assessed by staining with different fluorescent reagent DAPI, PI, Mito-Tracker Green and DCFH-DA. Meanwhile, the tested complexes up-regulated the expression levels of caspase-3 and Bax, down-regulated the Bcl-2 expression. In addition, they had no effect on zebrafish embryo survival, embryo hatching, embryonic movement, zebrafish malformation and zebrafish movement at below 0.5 µM. This suggests the complexes are potential candidates to be used in clinic for liver cancers.     

Steroidal alkaloids from Solanum erianthum and their anti-breast cancer properties

Two new glycoalkaloids, erianosides A (1) and B (2) along with five known compounds (3–7) were isolated from the leaves of Solanum erianthum. Their structures were elucidated from analyses of spectroscopic data and all isolates were tested for in vitro cytotoxic activity against human breast cancer cell lines (BT-549, MDA-MB-231, T74D, and MCF-7). Solasonine (5) and solamargine (6) were active against the aforementioned four cancer cell lines with IC₅₀ values of 27.26–35.89 and 5.84–10.13 μM, respectively. Erianoside A (1) (T74D: IC₅₀, 56.39 µM) and solasodine (3) (BT-549 and MDA-MB-231: IC₅₀, 59.15 and 75.63 µM, respectively) had moderate cytotoxic effects towards some cell lines in the panel.     

Design,synthesis and biological evaluation of matrine derivatives as potential anticancer agents

Using matrine (1) as the lead compound, a series of new 14-(N-substituted-2-pyrrolemethylene) matrine and 14-(N-substituted-indolemethylene) matrine derivatives was designed and synthesized for their potential application as anticancer agents. The structure of these compounds was characterized by ¹H NMR, ¹³C NMR and ESI-MS spectral analyses. The target compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (SMMC-7721, A549 and CNE2). The results revealed that compound A6 and B21 displayed the most significant anticancer activity against three cancer cell lines with IC₅₀ values in range of 3.42–8.05?μM, which showed better activity than the parent compound (Matrine) and positive control Cisplatin. Furthermore, the Annexin V-FITC/PI dual staining assay revealed that compound A6 and B21 could significantly induce the apoptosis of SMMC-7721 and CNE2 cells in a dose-dependent manner. The cell cycle analysis also revealed that compound A6 could cause cell cycle arrest of SMMC-7721 and CNE2 cells at G2/M phase.     

Bisstyryl constituents from the leaves of Miliusa sinensis

Miliusa sinensis Finet and Gagnep. have recently been subjected to numerous scientific studies pursuing its structure and biological properties. The chromatographic separation of the components from the methanolic extract of M. sinensis leaves yielded three new bisstyryls, namely, sinenbisstyryls A–C (1–3). The structures of the new compounds were determined via interpretation of their spectroscopic data. Of the isolated compounds, sinenbisstyryl A (1) exhibited cytotoxic activity against the A549 human lung, HepG2 human hepatocyte carcinoma, MCF7 human breast, and DU145 human prostate cancer cell lines, with IC₅₀ values of between 11.46 μM and 19.01 μM in four cases.     

Synthesis,cytotoxic activity,and tubulin polymerization inhibitory activity of new pyrrol-2(3H)-ones and pyridazin-3(2H)-ones

A series of new pyrrol-2(3H)-ones 4a-f and pyridazin-3(2H)-ones 7a-f were synthesized and characterized using different spectroscopic tools. Some of the tested compounds revealed moderate activity against 60 cell lines. The E form of the pyrrolones 4 showed good cytotoxic activity than both the Z form and the corresponding open amide form. Furthermore, the in vitro cytotoxic activity against HepG2 and MCF-7 cell lines revealed that compounds (E)4b, 6f and 7f showed good cytotoxic activity against HepG2 with IC₅₀ values of 11.47, 7.11 and 14.80 μM, respectively. Compounds (E)4b, 6f, 7d and 7f showed a pronounced inhibitory effect against cellular localization of tubulin. Flow cytometric analysis indicated that HepG2 cells treated with (E)4b showed a predominated growth arrest at the S-phase compared to that of G2/M-phase. Molecular modeling study using MOE® program indicated that most of the target compounds showed good binding of β-subunit of tubulin with the binding free energy (dG) values about −10 kcal/mole.     

Cytotoxic terpenoids from the stem bark of Taxus wallichiana

Chemical study of the stem bark of Taxus wallichiana Zucc. afforded the isolation of two new cyclopenta[b]naphthalene terpenoids, wallichianones A (1) and B (2) and 13 taxane diterpenoids, baccatin III (3), 10-deacetylbaccatin III (4), baccatin IV (5), 1-dehydroxybaccatin IV (6), 1-deoxybaccatin VI (7), taxol (8), 10-deacetyltaxol (9), 7-epi-10-deacetyltaxol (10), taxol-7-xyloside (11), 7-xylosyl-10-deacetyltaxol C (12), cephalomannine (13), 10-deacetylcaphalomannine (14), and 7-epi-10-deacetylcephalomannine (15). Their structures were identified by comprehensive analyses of the spectroscopic methods, including NMR and mass spectra. The absolute configurations of 1 and 2 were clarified by time-dependent density functional theory (TD-DFT) electronic circular dichroism (ECD) spectroscopic analyses. Compounds 3 and 7–15 showed cytotoxicity against all five human cancer cell lines, including lung (SK-LU-1), liver (HepG2), breast (MCF7), skin (SK-Mel-2), and prostate (LNCaP), with IC₅₀ values ranging from 1.4 ± 0.2 to 88.1 ± 5.8 μM. Compounds 9–11, 14, and 15 were additionally cytotoxic against human embryonic kidney (HEK-293A) cell line (IC₅₀ = 14.5 ± 1.0–48.4 ± 1.0 μM), however, 13 was noncytotoxic toward this cell line. The positive control, ellipticine showed cytotoxicity against all the cell lines, with IC₅₀ values in a range of 1.5 ± 0.1–2.0 ± 0.3 μM. Preliminary analysis of the structural and cytotoxicity relationship of compounds 3–15 suggested that the phenylalanine substituent at C-13 may contribute an important role for the cytotoxicity of the taxane diterpenoids.     

Four new compounds with cytotoxic and neuroprotective activity from Notopterygium incisum

Phytochemical research on an extract of Notopterygium incisum yielded twenty-four compounds (1–24), including four new compounds 7, 10, 13 and 17. The structures of new compounds were elucidated by spectroscopic analysis, and the absolute configuration of 5 were assigned via Mosher's method. In addition, compounds 2, 9, 19 and 24 were analyzed by single crystal X-ray analysis for the first time. The new compound 7 exhibited remarkable cytotoxic activity against the human pancreatic cancer cell lines PANC-1, CAPAN-2, CFPAC-1, and SW1990 with IC₅₀ values of 6.25 ± 0.54, 7.74 ± 1.12, 6.68 ± 1.11, and 5.35 ± 0.33 μM, respectively. The primary mechanistic study indicated that 7 caused cell death probably due to induced defects in the mitotic process. Moreover, compounds 2 and 7-9 effectively protected against H₂O₂-induced neurotoxicity in the SH-SY5Y cells, and 1, 3, 6, 10, 11, 16 and 19 exhibited strong DPPH scavenging ability.     

Two new polycyclic polyprenylated acylphloroglucinols from Hypericum curvisepalum N. Robson

Phytochemical investigation of the whole plant of Hypericum curvisepalum led to the isolation of nine polycyclic polyprenylated acylphloroglucinols (1–9). Among them, curvisepalumiones A (1) and B (2) are two new compounds and their structures were elucidated based on extensive spectroscopic data analysis combined with Rh₂(OCOCF₃)₄-induced electronic circular dichroism experiment. Cytotoxic assay showed that all the tested compounds except for 1 was moderately cytotoxic against human hepatocarcinoma cell line SMMC-7721 cell line, while compounds 3 and 4 also exhibited cytotoxicity toward MGC-803 cells. In addition, compound 2 exhibited weak inhibitory activity against Bacillus subtilis.