Multidrug-resistant cancer cell susceptibility to cytotoxic quassinoids, and cancer chemopreventive effects of quassinoids and canthin alkaloids

Twenty-three quassinoids (1-23), which were isolated previously from Simaroubaceous plants, were evaluated for cytotoxicity against three multidrug-resistant cancer cell lines, KB-VIN, KB-7d, and KB-CPT. Nine compounds (2-7 and 9-11) showed significant cytotoxicity in all three cell lines. Compounds 1, 12-14, 17, and 20 demonstrated significant activity against the KB-7d and KB-CPT cell lines, and compounds 18, 19, and 23 revealed notable activity only against KB-7d cells. Structure-activity relationships were drawn based on these data. In addition, six quassinoid derivatives (24-29) and four canthin alkaloids (30-33), which were isolated from Brucea antidysenterica, were examined for their inhibitory effects on 12-O-tetradecanoylphorbol-13-acetate (TPA) induced Epstein-Barr virus early antigen (EBV-EA) activation as cancer chemopreventive agents. All of these compounds demonstrated significant inhibitory effects against EBV-EA activation.     

Two New Taxane Diterpenoids from Taxus yunnanensis

Five compounds were isolated from the bark of Taxus yunnanensis Cheng et L. K. Fu. Based on spectral IR, MS, 1H-NMR, 13C-NMR and physico-chemical constant analysis, they were identified as 7-epi-taxol B ( Ⅰ ), 1, 13-diacetoxy-10-deacetyl baccatin Ⅲ (Ⅱ ), taxol C-7-xylose (Ⅲ), taxol (Ⅳ), 3-epi-ursolic acid (Ⅴ). Compounds Ⅰ and Ⅱ were newly identified.     

Bioactivity of Lignans from Taxus baccata

Three lignan derivatives, (-)-taxiresinol (1), (-)-3'-demethylisolariciresinol-9'-hydroxyisopropylether (2) and (-)-3-demethylisolariciresinol (3), previously isolated from the heart-wood of Taxus baccata L. (Taxaceae) were investigated for cytotoxicity against the Oncology Cell Line Panel (breast, colon, ovary, prostate, lung and a normal adult bovine aortic endothelial cell line) as well as for antimicrobial activities. Besides, a chloroform-soluble portion of the ethanol extract from the heartwood of T. baccata was also tested for antimicrobial activities. Compounds 1 - 3 did not demonstrate much cytotoxic potency according to the reference drug etoposide. With the exception of compound 2, the other two lignans (1 and 3) and the chloroform extract were shown to possess antifungal activity, whereas only the chloroform extract exhibited antibacterial activity against Pseudomonas aeruginosa.     

Taxines from the needles of Taxus wallichiana.

A taxine, 5 alpha O-(3'-dimethylamino-3'-phenylpropionyl) taxinine M (1) together with two known compounds 7-O-acetyltaxine A (2) and 2 alpha-acetoxy-2' beta-deacetylaustrospicatine (3) were isolated from the needles of the Himalayan yew, Taxus wallichiana Zucc. Their structures were elucidated on the basis of the NMR spectral data, ESI-MS/MS analysis and chemical methods. Compounds 1 and 3 showed moderate cytotoxic activity against the lung cancer cell line A549 in vitro.     

Antitumor agents. Part 230: C4'-esters of GL-331 as cytotoxic agents and DNA topoisomerase II inhibitors

Three C4'-acyl derivatives (5-7) of GL-331 (4) were synthesized and evaluated for cytotoxic and DNA topoisomerase II (topo II) inhibitory activity. All three compounds were cytotoxic against KB and KB-7d cells. Compounds 5 and 7, but not 6, were potent inhibitors of the DNA topoisomerase II in vitro and this relative activity ranking was maintained for cytotoxicity, in vitro cell growth inhibition, and ability to induce cellular double-strand DNA breaks. These results provided new information on the structure-activity relationships of the C4' molecular area of 4-analogues.     

滇西北云南红豆杉群落物种生态位与种间联结

在对滇西北云南红豆杉(Taxus yunnanensis)群落的野外调查基础上,采用生态位宽度、生态位重叠和基于2× 2联列表的χ²检验、联结系数(AC)的方法,分析了群落种群间的相互关系。结果表明:物种的重要值与相对应的生态位宽度存在着极显著正相关;云南红豆杉、丽江铁杉(Tsuga forrestii)与青荚叶(Helwingia japonica)的生态位宽度大于其它种群;在1225个种对中有48.16%的生态位重叠值为0,同时χ²统计量中有4%为中性联结,说明群落中木本植物种群间资源利用性竞争较强。生态位宽度较大的种群间往往生态位重叠也较大;云南红豆杉与丽江铁杉之间的生态位重叠值要明显高于与其它种群的,Schoener指数为0.875。χ²检验表明云南红豆杉与其它种群之间表现为无联结。联结系数中显著负联结的种对要多于显著正联结,群落物种受到较大的外来干扰。联结系数与生态位重叠值之间存在极显著正相关,并能用Cubic指数建立回归方程模型。     

New taxane diterpenoid from seed of the Chinese yew, Taxus yunnanensis

A novel taxane diterpenoid with a rearranged 5/7/6-membered ring system was isolated from seeds of the Chinese yew, Taxus yunnanensis. Its structure was established as 9alpha,13alpha-diacetoxy-10beta-benzoxy-5alpha- cinnamoyl-11(1 5-->1)-abeotaxa-4(20),11-dien-15-ol on the basis of a spectroscopic analysis. Its relative stereochemistry is proposed from the results of NOESY experiments.     

Diterpenes and sesquiterpenes from the bark of Taxus yunnanensis

Two taxane-type diterpenes, 10beta-acetoxy-2alpha,5alpha,7beta,9alpha-tetrahydroxytaxa-4(20),11-dien-13-one and 2alpha-acetoxy-9alpha-benzoyloxy-5alpha,7beta,10beta,15-tetrahydroxy-11(15-->1)- abeotaxa-4(20),11-dien-13-one, and two new drimane-type sesquiterpenes, 1beta-acetoxy-7-drimen-11alpha-ol-12,11-lactone and 1beta-acetoxy-11,12-epoxy-6-drimen-8alpha,11alpha-diol, were isolated from the bark of Taxus yunnanensis together with 35 known taxane-type diterpenes, a known drimane-type sesquiterpene and a known flavanone.     

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.     

红豆杉内生真菌次生代谢物的分离鉴定及其抗菌活性 分析

以产紫杉醇类化合物的云南红豆杉内生真菌12.3.2为目标菌株,对其次生代谢物进行分离鉴定和抗菌活性研究。通过硅胶柱层析,共分离得到3个主要成分,红外光谱、质谱、核磁共振氢谱等光谱解析鉴定其分别为松柏烯、邻苯二甲酸二异辛酯、油酸乙酯。生物活性试验表明3种化合物对金黄色葡萄球菌、枯草杆菌、大肠杆菌、绿脓杆菌和白色链球菌这5种致病菌都有一定的抑制作用。其中松柏烯对金黄色葡球菌、枯草杆菌和白色念珠菌有较强的抑制作用。松柏烯是首次报道从植物内生真菌次生代谢物中分离得到,这为松柏烯的来源开辟了一条重要的途径,同时也为松柏烯的进一步开发利用奠定了基础。     

云南红豆杉内生真菌Talarom yces sp.T1BF的化学成分研究

采用色谱技术从云南红豆杉内生真菌Talaromyces sp.T1BF的PDA平板发酵物中分离得到4个化合物.经波谱数据分析及与文献对照,分别鉴定为5α,6α-环氧-24( R)-甲基胆甾-7,22-二烯-3β-醇(1)、醌茜素(2)、苔色酸(3)和间甲基苯酚(4).化合物1为首次从该属真菌中分离获得.     

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.     

Stimulation of taxol production and excretion in Taxus spp cell cultures by rare earth chemical lanthanum

The trivalent ion of a rare earth element, lanthanum, was tested for elicitor-like effects on taxol production in suspension cultures of four different Taxus spp cells. In T. yunnanensis cell cultures, the lanthanum ion at concentrations from 1.15 to 23.0 microM stimulated taxol production. The lanthanum ion also promoted taxol excretion by the T. yunnanensis cells considerably. The maximum stimulation of taxol production was achieved by the addition of 5.8 microM La3+ to the culture during mid-log growth phase, increasing the volumetric taxol yield by nearly threefold, from 2.61+/-0.37 to 9.89+/-1.92 mg l(-1) over a 28 day culture period. At higher concentrations, i.e. 23.1 and 46.2 microM, however, the lanthanum ion caused significant growth inhibition. For the other three Taxus cell lines, namely an embryo and a leave cell of T. chinensis and a stem cell of T. chinensis marv, the addition of lanthanum ion to the culture only had a significant effect on taxol production by the T. chinensis marv stem cells, increasing the volumetric yield by about threefold to 4.69+/-0.76 mg l(-1). These results suggest that lanthanum has elicitor-like effects on secondary metabolite synthesis of plant cell cultures.     

Pharmacokinetic synergy from the taxane extract of Taxus chinensis improves the bioavailability of paclitaxel

BackgroundTaxus chinensis (Pilger) Rehd is widely distributed in China and the northern hemisphere, and the most popular medicinal component isolated from Taxus chinensis is paclitaxel (PTX), which has now become the first-line chemotherapeutic drug for breast cancer and ovarian cancer. Oral administration of pure PTX as a potential anti-cancer agent is compromised by low bioavailability.Hypothesis/purposeIn the clinical practice of traditional Chinese medicine, drug co-administration in the form of mixtures or formula could achieve pharmacokinetic/pharmacodynamic synergies. In this study, we aimed to investigate whether there exist any ‘inherent’ phytochemical synergy from Taxus chinensis extract that could improve PTX bioavailability.Study designPharmacokinetic study of PTX after oral administration of Taxus chinensis extracts or single PTX was performed. In addition, comparative cytotoxic studies were carried out on the MCF-7 breast cancer cell lines.MethodsThe plasma concentrations of PTX were determined using a validated high performance chromatography tandem mass spectrometry method. The cytotoxicity was compared using the MTT assay.ResultsOral administration of taxane fractions isolated from Taxus chinensis (containing 17.2% PTX) could achieve remarkably higher blood concentration and systemic exposure of PTX in rats, while the retention of PTX was significantly improved. Further tissue distribution analysis revealed that the penetration of PTX into major tissues was drastically increased compared with that of single PTX. In addition, in MCF-7 cells, the co-existing components in taxane mixtures could strengthen the inhibitory effects of PTX on tumor cell proliferation.ConclusionTogether, these results support that administration of PTX in the form of taxane mixtures may become a novel approach to improve the poor bioavailability of PTX. Moreover, the inherent synergy from Taxus chinensis taxane extracts promises a novel strategy to strengthen PTX efficacy.     

Antitumor agents. Part 235: Novel 4'-ester etoposide analogues as potent DNA topoisomerase II inhibitors with improved therapeutic potential

Eight 4'-ester epipodophyllotoxin derivatives (9-16) were designed and synthesized with the aim to overcome drug-resistance and improve water-solubility simultaneously. These compounds were superior to etoposide (1) in causing cellular protein-linked DNA breaks and inhibiting KB and 1-resistant KB-7d cell replication. Compounds 9 and 10 showed significant inhibitory activity against DNA topoisomerase II in vitro. Compound 10 also exhibited an in vitro DNA cleavage pattern similar to that of GL-331 (5). A hypothetical model on the action mode of 1-analogues is proposed based on the results.     

Taxane diterpenoids from the bark of Taxus yunnanensis

Further investigation on the alcohol extract of the barks of Taxus yunnanensis led to the isolation of four taxoids, namely, 7beta-xylosyl-taxol D, taxuyunnanines P, Q and R, along with the known taxuyuntin G (2). Four are rearranged taxoids with an 11(15-->1)-abeotaxoid skeleton and an opened oxetane ring moiety. Structures were determined by spectroscopic and chemical means.     

Triterpenoid saponins from Xanthoceras sorbifolia Bunge and their inhibitory activity on human cancer cell lines

Xanthoceras sorbifolia Bunge is widely used as healthy food material and folk medicine in China. Phytochemical investigation on its seeds oil leavings has led to the isolation and identification of seven new oleanane-type triterpenoid saponins named sorbifoliasides A-F (1-6) and bunkankasaponin F (7), along with five known ones (8-12). The structures of the new compounds were elucidated through spectroscopic analysis and chemical derivatization. Among the isolated compounds, 16-oxo-3, 28-O-bidesmosidic triterpenoid saponins (2, 3, 5) were isolated from this plant for the first time. The cytotoxicity of all compounds against the ten selected human cancer cell lines was assayed. Compounds 7 and 9 showed significant activity against all the ten cancer cell lines (IC(50) <10μM), while compounds 8, 10 and 11 exhibited moderate activity against most of these cancer cell lines.     

南方红豆杉内生及根际放线菌多样性及其生物活性

【目的】研究药用植物南方红豆杉内生及根际土壤放线菌的多样性及其抑菌、抗肿瘤等重要生物活性并获得一些具有强抑制植物病原真菌以及抗肿瘤等重要生物活性的菌株。【方法】选择7种培养基从南方红豆杉及其根际土壤中分离放线菌,对链霉菌进行形态学分类,去重复后对其进行抑制植物病原真菌以及抗肿瘤活性的筛选并对高活性菌株进行初步鉴定。对部分菌株进行16S rRNA基因测序分析研究其多样性。【结果】研究共分离得到277株放线菌,经去重复后剩余111株放线菌,可归类到6个亚目、7个科、8个属。其中链霉菌可分为10个类群。生物活性研究结果显示:30.9%的菌株具有抑制植物病原真菌活性,其中6株放线菌对多种植物病原真菌显示了强的抑菌活性。分别有44.1%和33.3%的菌株对胃癌肿瘤细胞株SGC-7901和肺癌肿瘤细胞株NCI-H460的抑制率在40%以上。【结论】药用植物南方红豆杉及其根际土壤蕴含种类丰富的放线菌资源,具有良好的生物学活性。菌株KLBMP 2170具有显著的抑菌以及抗肿瘤活性,值得我们去进一步研究。     

Screening of Taxol-producing fungi based on PCR amplification from Taxus

Genes coding for 10-deacetylbaccatin III-10-O-acetyl transferase and C-13 phenylpropanoid side chain-CoA acyltransferase were used as molecular markers for screening of Taxol-producing endophytic fungi. Using PCR, three out of 90 endophytic fungi, isolated from Taxus x media and Taxus yunnanensis, gave positive results. These 3 strains, when grown in 300 ml potato/dextrose liquid medium at 25°C for 10 days, contained 100–160 μg Taxol/g dry wt of mycelium. Peng Zhang and Peng-peng Zhou contributed equally to this work.     

Semi-synthesis of an O-glycosylated docetaxel analogue

A 7beta-O-glycosylated docetaxel analogue was semi-synthesized from 9-dihydro-13-acetylbaccatin III, the most abundant taxane isolated from the needles of Taxus canadensis. It was shown to be more bioactive than paclitaxel according to the tubulin assay. It had a reduced potency in the MCF7 cell line cytotoxicity assay compared to paclitaxel, but it demonstrated better activity against the drug resistant cell line MCF7-ADR. In addition, the presence of one sugar moiety on C-7 doubled the water solubility versus that of paclitaxel.