Cytotoxic triterpenoids from the root bark of Helicteres angustifolia

Three new triterpenoids, 3beta-acetoxy-27-[(E)-cinnamoyloxy]lup-20(29)-en-28-oic acid methyl ester (1), 3beta-acetoxy-27-[(4-hydroxybenzoyl)oxy]lup-20(29)-en-28-oic acid (2), and 3beta-acetoxy-27-[(4-hydroxybenzoyl)oxy]olean-12-en-28-oic acid methyl ester (3), together with nine known triterpenoids, 4-12, were isolated from the root bark of Helicteres angustifolia. The structures of these compounds were established on the basis of spectroscopic methods including 2D-NMR experiments. All twelve compounds were tested for their cytotoxic activities against human colorectal cancer (COLO 205), human hepatoma (Hep G2), and human gastric cancer (AGS) cell lines in vitro. Among them, compounds 2, 3, 3beta-O-[(E)-coumaroyl]betulinic acid (6), and pyracrenic acid (7) showed significant cytotoxic activities against human cancer cells COLO 205 and AGS.     

Oleanane glycosides from the roots of Alhagi maurorum

Three new oleanane-type triterpene glycosides (1–3), along with four known compounds (4–7) glycosides, were isolated from the roots of Alhagi maurorum. Their structures were elucidated by 1D and 2D-NMR experiments as well as ESI-MS analysis. The antiproliferative activity of the isolated compounds was evaluated against a small panel of cancer cell lines including human breast cancer (MCF-7), human lung adenocarcinoma (A549), human prostate cancer (PC-3) and human leukemia (U937) cell lines. None of the tested compounds, in a range of concentrations between 1 and 50 μM, caused a significant reduction of the cell number.     

海洋真菌Penicillium sp. WP-13次级代谢产物研究

本研究分析了海洋真菌Penicillium sp. WP-13的活性次级代谢产物。采用多种柱色谱技术对其发酵液的乙酸乙酯提取物进行分离纯化;根据波谱数据和理化常数分析,并结合文献比对鉴定单体化合物的结构;采用MTT法测定化合物对肿瘤细胞的细胞毒活性。从Penicillium sp. WP-13发酵液的乙酸乙酯提取物中分离鉴定了5个单体化合物,其中2个内酯类化合物为1-hydroxy-3,10-dimethoxy-8-methyl-6,11-dioxo-6,11-dihydrodibenzo[b,e]oxepine-9-carboxylicacid(1)和1,8-dihydroxy-10-methoxy-3-methyl-dibenzo[b,e]oxepine-6,11-dione(2); 3个蒽醌类化合物为endocrocinmethylester(3)、2-chloro-1,3,8-trihydroxy-6-methyl-9,10-anthracenedione (4)和emodin (5)。活性测试结果显示,化合物3和5均对人慢性髓原白血病细胞株K562、人肝癌细胞株BEL-740...     

茎花葱臭木化学成分的研究

从茎花葱臭木种子中分离得到5个化合物,经理化与波谱分析鉴定为β-谷甾醇(1)、没食子酸乙酯(2)、胡萝卜苷(3)、1-O-β-D-吡喃葡萄糖基-(2S,3S,4R,8Z)-2-N-(2 ′-羟基二十四烷酰氨基)十八二氧鞘氨-8-烯(4)和2,3,2″,3″-四氢穗花杉双黄酮(5).这5个化合物均首次从该植物中分离得到.其中化合物5进行细胞毒活性测试,没有显示抑制活性.     

Estrogenic constituents of the heartwood of Dalbergia parviflora

From the heartwood of Dalbergia parviflora, five compounds, dalparvin A (1), B (2), C (3), dalparvinol C (4), and neokhriol A (5), along with 11 known compounds, kenusanone G (6), cajanin (7), sophorol (8), alpinetin (9), hesperetin (10), 3'-O-methylorobol, odoratin, (2R)(3R)-2,3-trans 7-hydroxy-5-methoxydihydroflavonol, (6aR, 11aR)-3,8-dihydroxy-9-methoxypterocarpan, (6aR, 11aR)- vesticarpan, and methyl-3,4-dihydroxy-2-methoxybenzoate were isolated and characterized. Isolates were evaluated for their cell proliferation stimulatory activity against MCF-7, T-47D, and BT20 human breast cancer cell lines. Along with 7-10, two compounds 2 and 3 stimulated not only MCF-7, but also T-47D human breast cancer cell proliferation. Compound 6 had activity only against MCF-7 cells, and the activity of 7 was more than equivalent to that of daidzein. On the other hand, none of the isolates had any significant effects on BT20 cell proliferation, and these results indicated that the stimulative activity of these compounds was not general to any cell proliferations. Furthermore, these compounds were tested in the estrogen-responsive transient luciferase reporter assay.     

槲寄生中的化学成分及其抗肿瘤活性(Ⅰ)

从槲寄生75%乙醇提取物中分离得到4个化合物,应用波谱学方法鉴定它们的结构为尼克酰胺(1),乙酰胺(2),齐墩果酸(3),β-香树脂醇乙酸酯(4).其中,化合物1和2为首次从槲寄生属植物中分离得到.采用MIT法对化合物1～4进行体外抗肿瘤活性研究,结果显示化合物1、2和4对HO-8910人卵巢浆液性腺癌、SMMC7721人肝癌、T24人膀胱癌、HepG2人肝癌和SHG人神经胶质瘤细胞系没有细胞毒活性,化合物3则对这五种肿瘤细胞系有显著的抑制作用.     

Two New Norlignans and a New Lignanamide from Peperomia tetraphylla

Two new cyclobutane-type norlignans, methyl rel-(1R,2S,3S)-2-(7-methoxy-1,3-benzodioxol-5-yl)-3-(2,4,5-trimethoxyphenyl)cyclobutanecarboxylate (1), and methyl rel-(1R,2R,3S)-2-(7-methoxy-1,3-benzodioxol-5-yl)-3-(2,4,5-trimethoxyphenyl)cyclobutanecarboxylate (2), and a new lignanamide, 3-hydroxy-N-[2-(4-hydroxyphenyl)ethyl]-α-[4-(2-{N-[2-(4-hydroxyphenyl)ethyl]carbamoyl}ethenyl)-3-methoxyphenoxy]-4-methoxycinnamamide 4,8″-ether (3), along with five known amides, 4-8, were obtained from the whole plant of Peperomia tetraphylla. Their structures were elucidated mainly by the analysis of NMR and MS data. The new compounds 1-3 and the known compound 4 were tested for their cytotoxic activities against the HepG2 (human hepatocarcinoma), A549 (human lung cancer), and HeLa (human cervical cancer) cell lines. Compound 4 showed significant cytotoxicity against HepG2 cell lines with an IC(50) value of 9.4 ± 1.0?μM.     

Secondary metabolites from Commiphora opobalsamum and their antiproliferative effect on human prostate cancer cells

A cycloartane-type triterpenoid (1), an aliphatic alcohol glycoside (2), an eudesmane-type sesquiterpenoid (3), and a guaiane-type sesquiterpenoid (4) were isolated from the resinous exudates of Commiphora opobalsamum along with six known sesquiterpenoids (5-10). Their structures were established by extensive analysis of their 1D and 2D NMR spectroscopic data and chemical methods. The isolated compounds 1-3 and 5-9 were tested against human prostate cancer cell PC 3 and LNCaP. Among them, 1 and 2 showed moderate antiproliferative effects on human prostate cancer cell lines with IC50 values ranging from 5.7 to 23.6 microM; they were also able to inhibit the expression of androgen receptor (AR) in LNCaP cells. The six sesquiterpenoids were inactive in the bioassays.     

Semisynthesis and cytotoxic activities of andrographolide analogues

Andrographolide 1, a diterpenoid lactone of the plant Andrographis paniculata, known to possess antitumour activity in in vitro and in vivo breast cancer models was subjected to semisynthesis leading to the preparation of a number of novel compounds. These compounds exhibited in vitro antitumour activity with moderate to excellent growth inhibition against MCF-7 (breast) and HCT-116 (colon) cancer cells. Compounds 3,19-(2-chlorobenzylidene)andrographolide(5), 3,19-(3-chlorobenzylidene)andrographolide(6), 3,19-(3-fluorobenzylidene) andrographolide(7), 3,19-(4-fluorobenzylidene)andrographolide(8), 3,19-(2-fluorobenzylidene)andrographolide(10), 3,19-(2-chloro-5-nitrobenzylidene)andrographolide (21), 3,19-(4-chlorobenzylidene)andrographolide(30) and 3,19-(2-chloro-4-fluorobenzylidene) andrographolide(31) were also screened against 60 NCI (National Cancer Institute, USA) human tumour cell lines derived from nine cancer cell types.     

Synthesis and antiproliferative activity of 2-aryl-4-oxo-thiazolidin-3-yl-amides for prostate cancer

We have previously described serine amide phosphates (SAPs) as a novel class of cytotoxic agents for prostate cancer. Several of them showed potent cytotoxicity against human prostate cancer cell lines, but were not selective in non-tumor cells. To improve the selectivity and further enhance the potency, we designed a new series of 2-aryl-4-oxo-thiazolidin-3-yl amides. The current work describes synthesis, SAR, and biological evaluation of these compounds for their ability to inhibit the growth of prostate cancer cells. The antiproliferative effects of synthesized compounds were examined in five human prostate cancer cell lines (DU-145, PC-3, LNCaP, PPC-1, and TSU), and in RH7777 cells (negative controls). From this study, three potent compounds (8, 20, and 21) have been detected, which are effective in killing prostate cancer cells with improved selectivity compared to SAPs.     

Fungal metabolites of xanthohumol with potent antiproliferative activity on human cancer cell lines in vitro

Xanthohumol (1) and xanthohumol D (2) were isolated from spent hops. Isoxanthohumol (3) was obtained from xanthohumol by isomerisation in alkaline solution. Six metabolites were obtained as a result of transformation of xanthohumol (1) by selected fungal cultures. Their structures were established on the basis of their spectral data. One of them: 2″-(2′′′-hydroxyisopropyl)-dihydrofurano-[4″,5″:3′,4′]-4′,2-dihydroxy-6′-methoxy-α,β-dihydrochalcone (6) has not been previously reported in the literature. The antioxidant properties of hops flavonoids and xanthohumol derivatives were investigated using the 2,2′-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging method. The effects of these compounds on proliferation of MCF-7, PC-3 and HT-29 human cancer cell lines were determined by the SRB assay. With the exception of one metabolite, all tested compounds showed antiproliferative activity against the tested human cancer lines. α,β-Dihydroxanthohumol (4), obtained through the biotransformation of xanthohumol, showed higher antiproliferative activity against MCF-7 human breast carcinoma cell line than cisplatin, a widely used anticancer therapeutic agent, and a comparably high activity against PC-3 human prostate cancer cell line.     

Cytotoxic cardenolides from the stems of Periploca forrestii

Six new cardenolides, periforosides D-E (1-2), periforgenin C (3) and periforosides F-H (4-6), as well as 10 previously identified cardenolides (7-16) were isolated from the ethanol extract of the stems of Periploca forrestii. The structures of the new compounds were determined using extensive spectroscopic analyses including HRESI-MS, 1D and 2D NMR data. Evaluation of the cytotoxic activity of all the isolated compounds in five different human cancer cell lines indicated that compounds 2-6, 8, 9 and 12-16 have potent activity.     

Dihydroxyxanthones prenylated derivatives: synthesis, structure elucidation, and growth inhibitory activity on human tumor cell lines with improvement of selectivity for MCF-7

The synthesis, structure elucidation, and antitumor activity of 11 xanthones are reported, being the compounds 3, 4, 6-8, and 9 described for the first time. Xanthones 1 and 2 were used as building blocks to obtain the prenylated derivatives 3-8. Prenylation was carried out using prenyl bromide in alkaline medium. Dihydropyranoxanthones 9-11 were obtained from compounds 4 and 5 by an oxidative ring closure. The structure of the compounds was established by IR, UV, MS, and NMR ((1)H, (13)C, COSY, HSQC, and HMBC) techniques and for compounds 4, 6, and 11 the structure was confirmed by X-ray crystallographic analysis. The effect of the 11 xanthones on the in vitro growth of four human tumor cell lines, MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer), SF-268 (central nervous system cancer), and UACC-62 (melanoma) is also described.     

Photochemical synthesis and anticancer activity of barbituric acid,thiobarbituric acid,thiosemicarbazide, and isoniazid linked to 2-phenyl indole derivatives

2-Phenyl-1H-indole-3-carbaldehyde-based barbituric acid, thiobarbituric acid, thiosemicarbazide, isoniazid, and malononitrile derivatives were synthesized under photochemical conditions. The antitumor activities of the synthesized compounds were evaluated on three different human cancer cell lines representing prostate cancer cell line DU145, Dwivedi (DWD) cancer cell lines, and breast cancer cell line MCF7. All the screened compounds possessed moderate anticancer activity, and out of all the screened compounds, 5-{1[2-(4-chloro-phenyl)2-oxo-ethyl]-2-phenyl-1H-indole-3-ylmethylene}-2-thioxo-dihydro-pyrimidine-4,6-dione (2b) and 5-{1[2-(4-methoxy-phenyl)2-oxo-ethyl]-2-phenyl-1H-indole-3-ylmethylene}-2-thioxo-dihydro-pyrimidine-4,6-dione (2d) exhibited marked antitumor activity against used cell lines. Additionally, barbituric acid derivatives were selective to inhibit cell line DWD and breast cancer cell lines.     

Cyclopentenediones, inhibitors of farnesyl protein transferase and anti-tumor compounds, isolated from the fruit of Lindera erythrocarpa Makino

Four cyclopentenediones, farnesyl protein transferase inhibitors, and anti-tumor compounds were isolated from the methanolic extract of the fruits of Lindera erythrocarpa Makino (Lauraceae). The structure of the compounds was determined by spectral data including NMR and mass spectrometry, and cyclopentenediones such as methyllinderone (1), methyllucidone (2), lucidone (3), and linderone (4) were identified by comparing their reported spectral data with that of the literature values. Compounds 1-4 inhibited farnesyl protein transferase with IC50 value of 55.3+/-4.1, 42+/-1.9, 103+/-5.1, and 40+/-3.5 microM, respectively. Isolated compounds also inhibited the growth of various human cancer cell lines in a dose-dependent manner. Especially, Compounds 1 and 2 selectively inhibited the growth of H-ras-transformed rat-2 cell lines in comparison with normal rat-2 cells with a GI50 value of 0.3 and 0.85 microM, respectively. Methyllucidone strongly inhibited the growth of human cancer cells and colon tumor xenografted in nude mice. The anti-tumor effects of the compound were further confirmed with caspase-3 activation and degradation of PARP. The results suggest that methyllucidone can be a potential anti-cancer agent against H-ras-transformed tumor and will also be a good lead molecule for the development of anti-tumor drug.     

Synthesis and biological evaluation of rebeccamycin analogues modified at the imide moiety

Glycosylated indolocarbazoles related to the antibiotic rebeccamycin represent an important class of antitumour drugs. In the course of our structure-activity relationship studies, new rebeccamycin analogues modified at the imide moiety were synthesised. The antiproliferative activity of the compounds was evaluated on three human cancer cell lines, A2780 (ovarian cancer), H460 (lung cancer), and GLC4 (small-cell lung cancer). The in vitro cytotoxicity of compounds 2 and 4, characterised respectively by a 1,3-dioxolan and (1,3-dioxolan-4-yl)methylene groups linked to the imide moiety, was higher than the reference compound, edotecarin. The effect of compound 2 in inducing tumour regression in the A2780 xenograft model was also investigated.     

Antitumor activity of tetrahydroisoquinoline analogues 3-epi-jorumycin and 3-epi-renieramycin G

Analogues of the tetrahydroisoquinoline family of antitumor antibiotics, 3-epi-jorumycin (3) and 3-epi-renieramycin G (4), in addition to their respective parent natural products (-)-jorumycin (1) and (-)-renieramycin G (2) were evaluated against both human colon (HCT-116) and human lung (A549) cancer cell lines. (-)-Jorumycin (1) displayed potent growth inhibition with GI50 values in the low nanomolar range (1.9-24.3 nM), while compounds 2-4 were found to be substantially less cytotoxic (GI50 0.6-14.0 microM).     

Synthesis and antitumor activities of novel α-aminophosphonates dehydroabietic acid derivatives

A series of novel α-aminophosphonate derivatives containing DHA structure were designed and synthesized as antitumor agents. In vitro antitumor activities of these compounds against the NCI-H460 (human lung cancer cell), A549 (human lung adenocarcinoma cell), HepG2 (human liver cancer cell) and SKOV3 (human ovarian cancer cell) human cancer cell lines were evaluated and compared with commercial anticancer drug 5-fluorouracil (5-FU), employing standard MTT assay. The pharmacological screening results revealed that many compounds exhibited moderate to high levels of antitumor activities against the tested cancer cell lines and that most demonstrated more potent inhibitory activities compared with the commercial anticancer drug 5-FU. The action mechanism of representative compound 7c was preliminarily investigated by acridine orange/ethidium bromide staining, Hoechst 33258 staining, JC-1 mitochondrial membrane potential staining and flow cytometry, which indicated that the compound can induce cell apoptosis in NCI-H460 cells. Cell cycle analysis showed that compound 7c mainly arrested NCI-H460 cells in G1 stage.     

Semisynthesis and in vitro anticancer activities of andrographolide analogues

The plant Andrographis paniculata found throughout Southeast Asia contains Andrographolide 1, a diterpenoid lactone, which has antitumour activities against in vitro and in vivo breast cancer models. In the present study, we report on the synthesis of andrographolide derivatives, 3,19-isopropylideneandrographolide (2), 14-acetyl-3,19-isopropylideneandrographolide (3) and 14-acetylandrographolide (4), and their in vitro antitumour activities against a 2-cell line panel consisting of MCF-7 (breast cancer cell line) and HCT-116 (colon cancer cell line). Compounds 2 and 4 were also screened at the US National Cancer Institute (NCI) for their activities against a panel of 60 human cancer cell lines derived from nine cancer types. Compound 2 was found to be selective towards leukaemia and colon cancer cells, and compound 4 was selective towards leukaemia, ovarian and renal cancer cells at all the dose-response parameters. Compounds 2 and 4 showed non-specific phase of the cell cycle arrest in MCF-7 cells treated at different intervals with different concentrations. NCI's COMPARE and SOM mechanistic analyses indicated that the anticancer activities of these new class of compounds were not similar to that of standard anticancer agents, suggesting novel mechanism(s) of action.     

Differential activation of wild-type and variant forms of estrogen receptor alpha by synthetic and natural estrogenic compounds using a promoter containing three estrogen-responsive elements

Structure-dependent estrogen receptor alpha (ER alpha) agonist and antagonist activities of synthetic and natural estrogenic compounds were investigated in human HepG2, MDA-MB-231 and U2 cancer cell lines. Compounds used in this study include 4'-hydroxytamoxifen, ICI 182,780, bisphenol-A (BPA), 2',4',6'-trichloro-4-biphenylol (3Cl-PCB-OH), 2',3',4',5'-tetrachloro-4-biphenylol (4Cl-PCB-OH), p-t-octylphenol, p-nonylphenol, naringenin, kepone, resveratrol, and 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE). Cells were transfected with a construct (pERE(3)) containing three tandem estrogen responsive elements (EREs) and either wild-type estrogen receptor alpha (ER-wt) or variants expressing activation function-1 (ER-AF1) or AF-2 (ER-AF2). The ER agonist activities of the synthetic mono and dihydroxy aromatic compounds are comparable in all three-cell lines, whereas the activities of naringenin, kepone and resveratrol are dependent on cell context and expression of wild-type or variant forms of ER alpha. In contrast, the ER antagonist activities for these compounds were highly complex and, with the exception of 3Cl-PCB-OH, all compounds inhibited E2-induced wild-type or variant ER action. Results of this in vitro study suggest that the estrogenic and antiestrogenic activity of structurally diverse synthetic and natural estrogenic compounds is complex, and this is consistent with published data that often give contradictory results for these compounds.