Novel biologically active bibenzyls from Bauhinia saccocalyx Pierre

Four new bibenzyls, bauhinols A-D (1-4), together with the two known bibenzyls 5 and 6, were isolated from the roots of Bauhinia saccocalyx, and their structures were elucidated by analyses of spectroscopic data. Bauhinol A (1) exhibits significant cytotoxicity towards NCI-H187 (small-cell lung cancer), BC (breast cancer), and KB (oral-cavity cancer) cell lines, with IC50 values of 2.7-4.5 microg/ml. Bauhinol B (2) is cytotoxic against NCI-H187 (IC50 = 1.1 microg/ml) and BC (IC50 = 9.7 microg/ml) cell lines, but inactive toward the KB cell line (at 20 microg/ml). Compound 2 also is mildly antifungal towards Candia albicans (IC50 = 28.9 microg/ml). Bibenzyl 6 is active against NCI-H187 (IC50 = 14.1 microg/ml) and BC (IC50 = 4.0 microg/ml) cells, but inactive (at 20 microg/ml) toward the KB cell line. Compounds 1, 2, and 6 show mild antimycobacterial activities, with MIC values of 25-50 microg/ml, but are inactive at 20 microg/ml against the K1 malarial parasite strain (Plasmodium falciparum). While bauhinol A (1) is inactive against cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2), compounds 2 and 6 inhibit both COX-1 and COX-2, with IC50 values comparable to those of the standard drug, aspirin (Table 3).     

Inhibitory effects of ethyl acetate extract of Cordyceps sinensis mycelium on various cancer cells in culture and B16 melanoma in C57BL/6 mice

The cultivated mycelium of a Cordyceps sinensis (Cs) fungus was sequentially extracted by petroleum ether (PE), ethyl acetate (EtOAc), ethanol (EtOH) and hot water. All solvent extracts except hot water extract showed a significant and dose-dependent inhibitory effect on the proliferation of four cancer cell lines, MCF-7 breast cancer, B16 mouse melanoma, HL-60 human premyelocytic leukemia and HepG2 human hepatocellular carcinoma, with IC(50) values below 132 microg/ml. The EtOAc extract, in particular, had the most potent effect against all four cancer cell lines, with IC(50) between 12 microg/ml (on B16) and 45 microg/ml (on MCF-7). In contrast, it had much lower cytotoxicity against normal mouse bone marrow cells. The EtOAc extract contained carbohydrates, adenosine, ergosterol and trace amount of cordycepin, of which ergosterol and related compounds were identified as a major class of active constituents contributing to the in vitro cytotoxicity. In an animal test, the EtOAc extract showed significant inhibiting effect on B16-induced melanoma in C57BL/6 mice, causing about 60% decrease of tumor size over 27 days. Our results suggest that the EtOAc extract of Cs fungal mycelium has strong anti-tumor activity and is a potential source of natural anti-tumor products.     

Ixorapeptide I and ixorapeptide II, bioactive peptides isolated from Ixora coccinea

Two novel derivatized peptides, designated as ixorapeptide I (1) and ixorapeptide II (2), in addition to 28 other known compounds, were isolated from the MeOH extract of Ixora coccinea using bioassay-guided fractionation. The structures of metabolites 1 and 2 were determined by interpretation of the spectroscopic data and Marfey's method. Compound 1 exhibited selective potency against Hep3B liver cancer cell line with an IC(50) value of 3.36 μg/mL, and compound 2 did not show notable cytotoxicity toward cancer cell lines but could inhibit superoxide anion generation and elastase release with IC(50) values of 0.21 and 0.27 μg/mL, respectively. Moreover, kaempferol and luteolin from this plant showed inhibition with IC(50) values of 3.55 and 2.56 μg/mL, respectively on platelet aggregation induced by collagen.     

Design, synthesis and cytotoxic activity of novel spin-labeled rotenone derivatives

Three series of novel spin-labeled rotenone derivatives were synthesized and evaluated for cytotoxicity against four tumor cell lines, A-549, DU-145, KB and KBvin. All of the derivatives showed promising in vitro cytotoxic activity against the tumor cell lines tested, with IC(50) values ranging from 0.075 to 0.738μg/mL. Remarkably, all of the compounds were more potent than paclitaxel against KBvin in vitro, and compounds 3a and 3d displayed the highest cytotoxicity against this cell line (IC(50) 0.075 and 0.092μg/mL, respectively). Based on the observed cytotoxicity, structure-activity relationships have been described.     

Two new taxoids from Taxus chinensis

Two new taxoids, 2,20-O-diacetyltaxumairol N (1) and 14beta-hydroxy-10-deacetyl-2-O-debenzoylbacatin III (2), were isolated from the needles and stems of Taxus chinensis. Their structures were determined on the basis of extensive 1D- and 2D-NMR-spectral analysis. Compound 1 showed weak cytotoxicity activity against T-24 (IC50 = 34 microg/ml) and QGY-7701 (IC50 = 22 microg/ml) cancer lines. Compound 2 showed no obvious cytotoxicity activity against T-24 (IC50 > 100 microg/ml) and QGY-7701 (IC50 > 100 microg/ml) cancer lines.     

Analogs of the marine alkaloid makaluvamines: synthesis, topoisomerase II inhibition, and anticancer activity

Twelve analogs of makaluvamines have been synthesized. These compounds were evaluated for their ability to inhibit the enzyme topoisomerase II. Five compounds were shown to inhibit topoisomerase catalytic activity comparable to two known topoisomerase II targeting control drugs, etoposide and m-AMSA. Their cytotoxicity against human colon cancer cell line HCT-116 and human breast cancer cell lines MCF-7 and MDA-MB-468 has been evaluated. Four makaluvamine analogs exhibited better IC(50) values against HCT-116 as compared to control drug etoposide. One analog exhibited better IC(50) value against HCT-116 as compared to m-AMSA. All 12 of the makaluvamine analogs exhibited better IC(50) values against MCF-7 and MDA-MB-468 as compared to etoposide as well as m-AMSA.     

Cytotoxic activity of some marine brown algae against cancer cell lines

The aim of this study was to investigate the in vitro cytotoxic activity of total extract of MeOH (70%) and partition fractions of hexan, chloroform (CHCL3), ethylacetate (EtOAc) and MeOH-H2O of brown algae species (Sargassum swartzii, Cystoseira myrica, Colpomenia sinuosa) found in the Persian Gulf against in different cell lines including HT-29, Caco-2, T47D, MDA-MB468 and NIH 3T3 cell lines by MTT and AnnexinV-PI assay. The hexan fraction of S. swartzii and C. myrica showed selective cytotoxicity against proliferation of Caco-2 cells (IC50 < 100 μg/ml) T47D cell line (IC50<100 μg/ml), respectively. S. swartzii and C. myrica were also observed for increasing apoptosis in Caco-2 and T47D cells. Total extract and fractions of C. sinuosa did not show any significant cytotoxicity against the studied cell lines. MDA-MB468 cells were more sensitive to C. myrica than was T47D (IC50 99.9 ± 8.11 vs. 56.50' ± 0.88). This reflects an estrogen receptor independent mechanism for cytotoxicity of the extract. The IC50 of the hexan fraction of C. myrica on T47D parent cells was lower than it was on T47D-TR cells (IC50 99.9 ± 8.11 vs. 143.15 ± 7.80). This finding suggests a role for the MDR-1 in the development of possible future tolerance to the extract.     

牛至油体外抗肿瘤活性研究

目的观察牛至油对肿瘤细胞株的生长抑制作用。方法采用MTT法检测不同浓度的牛至油对体外培养的多种肿瘤细胞株的生长抑制作用,计算半数抑制浓度(IC50)。结果不同浓度牛至油作用后,人肝癌细胞系HepG2、人子宫颈癌细胞系JTC-26和肺癌细胞系A549出现增殖阻滞。MTT法确定牛至油对肝癌HepG2的IC50为118μg/ml;人子宫颈癌JTC-26的IC50为118μg/ml;肺癌A549的IC50为59μg/ml。结论牛至油具有体外抗肿瘤活性。     

Potent antitumor activity of synthetic 1,2-Naphthoquinones and 1,4-Naphthoquinones

Rhinacanthone (1) and two 1,2-pyranonaphthoquinones (2,3) were synthesized and found to show very potent cytotoxicity against three cancer cell lines (KB, HeLa and HepG(2)) with IC(50) values of 0.92-9.63 microM, whereas the corresponding hydroxylated derivative 4 had reduced cytotoxicity (IC(50) values of 7.61-24.13 microM). Three 1,2-furanonaphthoquinone derivatives (5-7) were also synthesized with similar cytotoxicity as 1,2-pyranonaphthoquinones. In comparison to 1,2-naphthoquinones, six 1,4-naphthoquinones derivatives fused with pyran ring (8-10) and furan ring (11-13) were synthesized and they showed less cytotoxicity or inactive to the cancer cell lines. Moreover, compound 13 had significant cytotoxicity against HeLa cell line (IC(50) value of 9.25 microM) while it showed no toxic to vero cell.     

A new Hypocrea strain producing harzianum A cytotoxic to tumour cell lines

AIMS: To identify a new fungal strain, Hypocrea sp. F000527 producing a trichothecene metabolite, harzianum A, and to evaluate its cytotoxicity to tumour cell lines. METHODS AND RESULTS: A fungal strain, F000527, with cytotoxic activity was identified as a new Hypocrea strain based on morphological characteristics and internal transcribed spacers rDNA sequence data. Harzianum A was isolated from wheat bran culture by 50% acetone extraction, silica gel chromatography, Sephadex LH-20 chromatography and HPLC. The chemical structures were determined by ESI- or HRFAB-MS and (1)H and (13)C-NMR analyses. Harzianum A showed cytotoxicity to HT1080 and HeLa cell lines with IC(50) value of 0.65 and 5.07 ?g ml(-1) respectively. CONCLUSIONS: Harzianum A with a chemical formula of C(23)H(28)O(6) was isolated from a new Hypocrea strain and showed moderate to strong cytotoxicity to human cancer cell lines. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report of the production of cytotoxic harzianum A by a new Hypocrea strain.     

N-acetylglycoside of oleanolic acid (aridanin) displays promising cytotoxicity towards human and animal cancer cells,inducing apoptotic,ferroptotic and necroptotic cell death

BackgroundThe discovery of novel phytochemicals represents a reasonable approach to fight malignancies, especially those which are resistant to standard chemotherapy.PurposeWe evaluated the cytotoxic potential of a naturally occurring N-acetylglycoside of oleanolic acid, aridanin, on 18 cancer cell lines, including sensitive and drug-resistant phenotypes mediated by P-glycoprotein, BCRP, p53 knockout, deletion-mutated EGFR, or BRAF mutations. Furthermore, metastasizing B16/F10 cells, HepG2 hepatocarcinoma and normal AML12 hepatocytes were investigated. The mechanisms of aridanin-induced cell death was further investigated.MethodsThe resazurin reduction assay (RRA) was applied to evaluate the cytotoxicity, autophagy, ferroptotic and necroptotic cell death. CCRF-CEM leukemia cells were used for all mechanistic studies. A caspase-Glo assay was applied to evaluate the caspase activities. Flow cytometry was applied for the analyses of cell cycle (PI staining), apoptosis (annexin V/PI staining), mitochondrial membrane potential (MMP; JC-1) and reactive oxygen species (ROS; H₂DCFH-DA).ResultsAridanin and doxorubicin (positive control) inhibited the proliferation of all cancer cell lines tested. The IC₅₀ values for aridanin varied from 3.18 µM (CCRF-CEM cells) to 9.56 µM (HepG2 cells). Aridanin had considerably lower IC₅₀ values than that of doxorubicin against multidrug-resistant CEM/ADR5000 cells and melanoma cell lines (MaMel-80a, Mel-2a, MV3, and SKMel-505). Aridanin induced apoptosis in CCRF-CEM cells through increase of ROS levels and MMP breakdown, and to a lesser extent via caspases activation. Aridanin also induced ferroptotic and necroptotic cell death.ConclusionThe present study opens good perpectives for the use of this phytochemical as an anticancer drug to combat multi-facorial resistance to established chemotherapeutics.     

Studies on the secondary metabolites of a Pseudoalteromonas sp. isolated from sediments collected at the northeastern coast of Brazil

Continuing search for anticancer compounds from the marine environment, we have studied microorganisms that inhabit intertidal sediments of the northeastern Brazilian coast. Of the 32 strains isolated, 13 were selected for biological evaluation of their crude extracts. The acetate extract obtained from a Gram-negative bacterium was strongly active against cancer cell lines with IC(50) values that ranged from 0.04 (HL60 leukemia cells) to 0.26 μg/ml (MDA MB-435 melanoma cells). The bacterium was identified as a Pseudoalteromonas sp. based on 16S rRNA gene sequencing. A bioassay-guided fractionation of the active extract led to the isolation of prodigiosin, a well-known tripyrrole red pigment with immunosuppressive and anticancer activities. Further experiments with ErbB-2 overexpressing cell lines, including HB4a-C3.6 (moderate overexpression), HB4a-C5.2 (high overexpression), and the parental HB4a cell line, were performed. Prodigiosin was moderately active toward HB4a cells with an IC(50) of 4.6 μg/ml, while it was 115 and 18 times more active toward HB4a-C3.6 cells (IC(50) of 0.04 μg/ml) and HB4a-C5.2 (IC(50) of 0.26 μg/ml) cells, respectively. These data suggest that, in spite of its previously described apoptosis-inducing properties, prodigiosin can selectively recognize cells overexpressing ErbB-2, which could be highly appealing in human breast cancer therapy.     

Evaluation of in vitro alpha-glucosidase inhibitory,antimicrobial, and cytotoxic activities of secondary metabolites from the endophytic fungus,Nigrospora sphaerica,isolated from Helianthus annuus

This study aimed to evaluate alpha-glucosidase inhibition and antimicrobial activity as well as cytotoxic activity of extracts from the endophytic fungus, Nigrospora sp., isolated from leaves of Helianthus annuus, which is widely cultivated for food and used as a medicinal plant. The fungus (TSU-CS003) was identified based on internal transcribed spacer ribosomal DNA sequences and fungal biomass, and fermentation broth was subjected to extraction by solvents (hexane and ethyl acetate). All extracts were tested for their antimicrobial activity, alpha-glucosidase inhibition, and cytotoxicity activity. In addition, the active extract was analyzed by using gas chromatography mass spectrometry (GC-MS) TSU-CS003 was identified as Nigrospora sphaerica. The fermentation broth extract (BE) showed strong antimicrobial activity against Staphylococcus aureus and methicillin-resistant S. aureus (Gram-positive bacteria) with minimum inhibitory concentration (MIC) values in the range of 16–32 μg/mL and a few yeasts with MIC values ranging from 64 to 128 μg/mL, especially Talaromyces marneffei with an MIC value of 4 μg/mL. The effects of BE were observed by SEM. The results showed that this extract affected the cell morphology of T. marneffei. The half-maximal inhibitory concentration (IC50) of BE from alpha-glucosidase inhibition was recorded as 17.25 μg/mL and also showed significant cytotoxicity against A549 human cancer cell lines with an IC50 value of 22.41 μg/mL. Furthermore, BE was analyzed by using GC-MS and divided into three main compounds, including 5-pentyldihydrofuran-2(3H)-one, (Z)-methyl 4-(isobutyryloxy)but-3-enoate, and 2-phenylacetic acid. This was the first report of the endophytic fungus N. sphaerica from H. annuus. It is a potential source of active metabolites, which gave the strong antifungal activity, antioxidant activity, and cytotoxicity to A549 cancer cell lines.     

Acetonic extract of Buxus sempervirens induces cell cycle arrest, apoptosis and autophagy in breast cancer cells

Plants are an invaluable source of potential new anti-cancer drugs. Here, we investigated the cytotoxic activity of the acetonic extract of Buxus sempervirens on five breast cancer cell lines, MCF7, MCF10CA1a and T47D, three aggressive triple positive breast cancer cell lines, and BT-20 and MDA-MB-435, which are triple negative breast cancer cell lines. As a control, MCF10A, a spontaneously immortalized but non-tumoral cell line has been used. The acetonic extract of Buxus sempervirens showed cytotoxic activity towards all the five studied breast cancer cell lines with an IC(50) ranging from 7.74 μg/ml to 12.5 μg/ml. Most importantly, the plant extract was less toxic towards MCF10A with an IC(50) of 19.24 μg/ml. Fluorescence-activated cell sorting (FACS) analysis showed that the plant extract induced cell death and cell cycle arrest in G0/G1 phase in MCF7, T47D, MCF10CA1a and BT-20 cell lines, concomitant to cyclin D1 downregulation. Application of MCF7 and MCF10CA1a respective IC(50) did not show such effects on the control cell line MCF10A. Propidium iodide/Annexin V double staining revealed a pre-apoptotic cell population with extract-treated MCF10CA1a, T47D and BT-20 cells. Transmission electron microscopy analyses indicated the occurrence of autophagy in MCF7 and MCF10CA1a cell lines. Immunofluorescence and Western blot assays confirmed the processing of microtubule-associated protein LC3 in the treated cancer cells. Moreover, we have demonstrated the upregulation of Beclin-1 in these cell lines and downregulation of Survivin and p21. Also, Caspase-3 detection in treated BT-20 and T47D confirmed the occurrence of apoptosis in these cells. Our findings indicate that Buxus sempervirens extract exhibit promising anti-cancer activity by triggering both autophagic cell death and apoptosis, suggesting that this plant may contain potential anti-cancer agents for single or combinatory cancer therapy against breast cancer.     

Synthesis, antimycobacterial and antitumor activities of new (1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)methyl N,N-disubstituted dithiocarbamate/O-alkyldithiocarbonate derivatives

Reaction of 2-chloromethylsaccharin with substituted potassium dithiocarbamates and substituted potassium dithiocarbonates furnished (1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)methyl N,N-disubstituted dithiocarbamates (4-15) and (1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)methyl O-alkyldithiocarbonates (16-20). The new derivatives were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv. Compounds 4-13, 15, and 16-20 described herein showed moderate to good inhibitory activity. In particular, seven analogs 4, 5, 6, 13, and 7, 8, and 12 exhibited excellent MIC values of 1.56 and 0.78 microg/mL, respectively. Compounds 4, 5, 10, 12, 13, and 16 were selected and screened for antitumor activity. Among the tested compounds, 4 and 5 were found to be cytotoxic, especially against leukemia cell lines CCRF-CEM, HL-60(TB), RPMI-8226, and SR with log10GI50 values lower than -6.69, and against non-small cell lung cancer NCI-H522 cell line with log10GI50 values lower than -6.31. Compound 10 was cytotoxic against leukemia cell line HL-60(TB), whereas 16 displayed favorable cytotoxicity against ovarian cancer cell line OVCAR-3 with log10GI50 values of -6.31 and -7.45, respectively.     

Synthesis and antitumour activity of glycyrrhetinic acid derivatives

Glycyrrhetinic acid (GA) is one of many interesting triterpenoic acids showing anticancerogenic potential. GA is known to trigger apoptosis in tumour cell lines, although GA has a low cytotoxicity. In our study we were able to prepare derivatives of GA that show lowered the IC(50) values as determined by a sulforhodamine B (SRB) assay using 15 different human tumour cell lines. Thus, combining an ester group combined with the presence of an amino acid moiety led to a ca. 60-fold improved antitumor activity. Experiments on mouse embryonic fibroblasts (NiH3T3) revealed that these compounds showed a better selectivity for tumour cells compared to the parent compound GA. An apoptotic effect of some of these compounds was determined using an acridine orange/ethidium bromide (AO/EB) test and DNA laddering experiments.     

Abronione, a rotenoid from the desert annual Abronia villosa

A high-throughput phytochemical investigation of Abronia villosa afforded a new rotenoid designated abronione (1) along with the known compounds boeravinone C and lupeol. The structure of 1 was determined using NMR, MS, and optical analysis with < 400 μg of material. Compound 1 displayed moderate cytotoxicity against NCI-H460 and HL-60 human cancer cell lines with IC(50) values of 14 and 36 μM, respectively.     

Activity of three cytotoxic isoflavonoids from Erythrina excelsa and Erythrina senegalensis (neobavaisoflavone,sigmoidin H and isoneorautenol) toward multi-factorial drug resistant cancer cells

IntroductionResistance of cancer cells to chemotherapy has become a worldwide concern. Naturally occuring isoflavonoids possess a variety of biological activities including anti-cancer effects. The present study was aimed at investigating the cytotoxicity and the modes of action of three naturally occuring isoflavonoids, neobavaisoflavone (1), sigmoidin H (2) and a pterocarpan that is a special type of isoflavonoid, isoneorautenol (3) against a panel of nine cancer cell lines, including various sensitive and drug-resistant phenotypes.MethodsThe cytotoxicity of the compounds was determined using a resazurin reduction assay, whereas the caspase-Glo assay was used to detect the activation of caspases 3/7, caspase 8 and caspase 9 in cells treated with compounds 3. Flow cytometry was used for cell cycle analysis and detection of apoptotic cells, analysis of mitochondrial membrane potential (MMP) as well as measurement of reactive oxygen species (ROS).ResultsCompounds 3 showed significant cytotoxicity toward sensitive and drug-resistant cancer cell lines. Compounds 1 and 2 were selectively active, and IC50 values below 115 μM were obtained on 6/9 and 4/9 cell lines respectively with values ranging from 42.93 μM (toward CCRF-CEM cells) to 114.64 μM [against HCT116 (p53^+/+) cells] for 1 and 25.59 μM (toward U87MG) to 110.51 μM [against HCT116 (p53^+/+) cells] for 2. IC50 values ranging from 2.67 μM (against MDA-MB 237BCRP cells) to 21.84 (toward U87MG) were measured for compound 3 and between 0.20 μM (toward CCRF-CEM cells) and 195.12 μM (toward CEM/ADR5000 cells) for doxorubicin as control drug. BCRP-transfected MDA-MB-231 cells, HCT116 (p53^+/+) and U87MG.ΔEGFR cells were hypersensitive (collateral sensitive) to compound 3 as compared to their counterpart cell lines. Compound 3 induced apoptosis in CCRF-CEM cells via activation of caspases 3/7, 8 and 9 as well as the loss of MMP and increased ROS production.ConclusionsThe cytotoxicity of the studied isoflavonoids and especially the pterocarpan 3 deserve more detailed exploration in the future to develop novel anticancer drugs against sensitive and otherwise drug-resistant phenotypes.     

Anticancer and anti-inflammatory activities of 1,8-naphthyridine-3-carboxamide derivatives

Several 1,8-naphthyridine-3-carboxamide derivatives (8-23) were synthesized and tested for in vitro cytotoxicity against eight cancer cell lines and a normal cell line. Compound 12 exhibited high cytotoxicity (IC(50)=1.37microM) in HBL-100 (breast) cell line while compounds 17 (IC(50)=3.7microM) and 22 (IC(50)=3.0microM) have shown high cytotoxicity in KB (oral) and SW-620 (colon) cell lines, respectively. The synthesized 1,8-naphthyridine-3-carboxamides were also evaluated for anti-inflammatory and myeloprotective activities, indicated by modulation in cytokine and chemokine levels secreted by dendritic cells.     

Synthesis and potent antileukemic activities of 10-benzyl-9(10H)-acridinones

A novel series of 10-benzyl-9(10H)-acridinones and 1-benzyl-4-piperidones were synthesized and tested for their in vitro antitumor activities against CCRF-CEM cells. Assay-based antiproliferative activity study using CCRF-CEM cell lines revealed that the acridone group and the substitution pattern on the benzene unit had significant effect on cytotoxicity of this series of compounds, among which 10-(3,5-dimethoxy)benzyl-9(10H)-acridinone (3b) was found to be the most active compound with IC(50) at about 0.7 microM. Compound 3b was also found to have antiproliferative activity against two other human leukemic cell lines K562 and HL60 using the MTT assay. The antitumor effect of 3b is believed to be due to the induction of apoptosis, which is further confirmed by PI (Propidium iodide) staining and Annexin V-FITC/PI staining assay using flow cytometry analysis.