Torilin from Torilis japonica,as a new inhibitor of testosterone 5 alpha-reductase

The methanolic extract of the fruits of Torilis japonica showed a potent inhibition against 5 alpha-reductase activity in vitro. Bioassay-guided fractionation of the methanol extract of the fruits followed by repeated silica gel chromatography led to the isolation of an active principle and its structure was identified as torilin on the basis of spectroscopic data. Torilin (IC50 = 31.7 +/- 4.23 microM) showed a stronger inhibition of 5 alpha-reductase than alpha-linolenic acid (IC50 = 160.3 +/- 24.62 microM) but was weaker than finasteride. (IC50 = 0.38 +/- 0.06 microM). Simple guaiane-type compounds, such as (-)-guaiol and guaiazulene showed weak inhibitory effects on the 5 alpha-reductase activity with IC50 values of f 81.6 microM and 100.8 microM, respectively, while azulene was not active. These results suggest that both degrees of unsaturation and the side-chain in the guaiane skeleton are important for the manifestation of 5 alpha-reductase inhibition.     

Geniposide, an anti-angiogenic compound from the fruits of Gardenia jasminoides

The EtOH extract of gardenia (Gardenia jasminoides Ellis) fruits was previously found to possess potent anti-angiogenic activity in the chick embryo chorioallantoic membrane (CAM) assay. Bioassay-guided fractionation and purification of the EtOH extract yielded an active anti-angiogenic compound, which was determined to be an iridoid glucoside, geniposide, by spectral analyses. Geniposide showed anti-angiogenic activity in a dose-dependent manner. It also exhibited an inhibitory effect in the range of 25-100 microM on the growth of the transformed NIH3T3 cell line.     

Antiproliferative and apoptotic activities of extracts of Asclepias subulata

Abstract

Context: Asclepias subulata Decne. (Apocynaceae) is a shrub used in the Mexican traditional medicine for the treatment of cancer.

Objective: The objective of this study was to evaluate the antiproliferative activity of methanol extract of aerial parts of A. subulata and its fractions against different cancer cell lines. Additionally, we analyzed the mechanism of action of the active fractions.

Materials and methods: Methanol extract fractions were prepared by serial extraction with n-hexane, ethyl acetate, and ethanol. The antiproliferative activity of methanol extract and its fractions was evaluated, against several murine (M12.C3.F6, RAW 264.7, and L929) and human (HeLa, A549, PC-3, LS 180, and ARPE-19) cell lines by the MTT assay, using concentrations of 0.4–400?µg/mL for 48?h. Ethanol and residual fractions were separated using silica gel column. Apoptosis induction of cancer cells was evaluated by Annexin and JC-1 staining using flow cytometry.

Results: Methanol extract and its fractions showed antiproliferative activity against all human cancer cell lines tested. Methanol extract had the highest antiproliferative activity on A549 and HeLa cells (IC₅₀ values?<?0.4 and 8.7?µg/mL, respectively). Ethanol and residual fractions exerted significant antiproliferative effect on A549 (IC₅₀?<?0.4?µg/mL) and PC3 cells (IC₅₀ 1.4 and 5.1?µg/mL). Apoptotic assays showed that CEF7, CEF9, CRF6, and CRF5 fractions induced mitochondrial depolarization in A549 cells, 70, 73, 77, and 80%, respectively. Those fractions triggered the apoptosis mitochondrial pathway.

Conclusion: Our data show that A. subulata extracts have potent antiproliferative properties on human cancer cell lines. This plant should be considered an important source of potent anticancer compounds.     

Antiproliferative activity of diarylheptanoids from the seeds of Alpinia blepharocalyx

The 95% EtOH extract of the seeds of Alpinia blepharocalyx (Zingiberaceae) showed significant antiproliferative activity towards human HT-1080 fibrosarcoma and murine colon 26-L5 carcinoma cells. Chemical investigation of the extract led to the isolation of forty-four new (1-44) and one known (45) diarylheptanoids, eleven phenolic compounds (46-56) together with beta-sitosterol glucoside (57). Almost all the isolated compounds showed significant antiproliferative activity in a concentration-dependent manner. Among the compounds, epicalyxin F (17) exhibited the most potent activity against the proliferation of colon 26-L5 carcinoma cells with an ED50 value of 0.89 microM, while calyxin B (2) exhibited the most potent activity against human HT-1080 fibrosarcoma cells with an ED50 value of 0.69 microM. Moreover, calyxins B (2) and K (11), epicalyxins F (17), I (20) and K (22), 6-hydroxycalyxin F (25), blepharocalyxin B (27) and mixtures of 7 and epicalyxin G (18) and of calyxin J (10) and epicalyxin J (21) possessed more potent activity than a clinically used anticancer drug, 5-fluorouracil, towards HT-1080 fibrosarcoma cells. Analysis of the structure activity relationship suggested that the position of the attachment of a chalcone or a flavanone moiety does not affect the activity, although their presence in association causes a substantial enhancement of the antiproliferative activity. Moreover, the conjugated double bond of the chalcone moiety and the phenolic hydroxyl group potentiate the antiproliferative activity of the compounds.     

Antiproliferative activity of an aqueous mistletoe extract in human tumor cell lines and xenografts in vitro

The in vitro antiproliferative activity of an aqueous mistletoe extract (AME) with a defined content of bioactive mistletoe lectin (ML) was tested in 25 human tumor cell lines, including 20 solid and 5 hematological malignancies and 47 human tumor xenografts. The antiproliferative activity of AME was compared to that of the standard cytotoxic agent doxorubicin (CAS 23214-92-8, adriamycin, ADR) using the sulforhodamin B, propidium iodide and soft agar colony forming assays, respectively. AME was highly cytotoxic in solid human tumors with mean IC70 values in the range of 0.17-1 ng ML/ml (2.8-17 pmol bioactive ML). On a molar basis, AME was 3 to 4 logs more potent than ADR and showed differential cytotoxicity towards tumors of the breast, small cell and non-small cell lung, prostate and renal cell cancers. AME was also highly active in hematological malignancies with steep dose response curves resulting in mean IC70 values of 0.12 ng ML/ml (2 pmol). The acute lymphoblastic leukemia cell line HL-60 was the most sensitive, the histiocytic lymphoma cell line U937 the most resistant hematological malignancy. It is important to stress that AME did not induce a biologically relevant increase of cell proliferation in any of the tumor cell lines tested. Our data suggest that AME has in vitro antitumor profiles similar to those of classical anticancer agents. Clear dose-response relationships were found in all of the performed experiments and interesting differential cytotoxicity patterns were observed. Experiments with sensitive tumor types identified in these in vitro studies are currently ongoing in order to demonstrate the anticancer activity of AME in different animal tumor models.     

Atractyligenine chemistry,Part VI: Synthesis and biological activities of atractyligenine derivatives

Derivatives of atractyligenine, the aglycone of atractyloside, were tested in vitro for their antimicrobial and antiproliferative activity against K-562 (human chronic myelogeneous leukemia), HL-60 (human leukemia) and MCF-7 (human breast adenocarcinoma) cell lines. The most active compound showed IC50 values in the range 0.8-6.9 microM.     

Synthesis and cytotoxicity testing of novel 2-(3-substituted-6-chloro-1,1-dioxo-1,4,2-benzodithiazin-7-yl)-3-phenyl-4(3H)-quinazolinones

A new series of thirteen 2-[3-(substituted amino)-6-chloro-1,1-dioxo-1,4,2-benzodithiazin-7-yl]-3-phenyl-4(3H)-quinazolinones 4-16 were prepared in order to evaluate their cytotoxic activity against 12 human cancer cell lines. The bioassay indicated that the quinazolinone derivatives 5, 8-12, 15, and 16 possess cancer-cell growth-inhibitory properties. Compounds 5 and 12 showed a high level of selectivity for certain cell lines. The most active compounds 9, 10, 15, and 16 showed moderate antiproliferative activity and were approximately 4-fold less potent than cisplatin.     

Antiproliferative activity of Rhinacanthus nasutus (L.) Kurz extracts and the active moiety, Rhinacanthin C

Rhinacanthus nasutus (L.) Kurz (Acanthaceae) is a shrub widely distributed in South China and India. In this study, the antiproliferative activity of the ethanol extract of root and aqueous extract of leaves of R. nasutus, and the supposed active moiety rhinacanthin C was assessed in vitro using the human cervical carcinoma cell line HeLa, its MDR1-overexpressing subline Hvr100-6, human prostate carcinoma PC-3 cells and human bladder carcinoma T24 cells. Rhinacanthin C was chemically synthesized and its content in the R. nasutus extracts was determined by HPLC with a photodiode array detector. The antiproliferative activity of the R. nasutus extracts was also assessed in vivo using sarcoma 180-bearing mice. It was suggested that 1) the in vitro antiproliferative activity of rhinacanthin C was comparable with or slightly weaker than that of 5-FU, 2) rhinacanthin C showed antiproliferative activity for MDR1-overexpressing Hvr100-6 cells, similarly to parent HeLa cells, 3) the in vitro antiproliferative activity of the ethanol extract of root R. nasutus was due to rhinacanthin C, whereas that of the aqueous extract of leaves of R. nasutus was due to constituents other than rhinacanthin C, and 4) both of the R. nasutus extracts showed in vivo antiproliferative activity after oral administration once daily for 14 d.     

Antiproliferative activities of Garcinia bracteata extract and its active ingredient,isobractatin, against human tumor cell lines

In our cell based screening of antitumor ingredients from plants, the EtOH extract of Garcinia bracteata displayed antiproliferative effect against human lung adenocarcinoma A549 cells, human breast cancer MCF-7 cells, and human prostate cancer PC3 cells. Phytochemical investigation of this active extract produced nine ingredients, and their structures were established by analysis of MS and NMR spectra. Antiproliferative evaluation of isolated ingredients on A549, MCF-7 and PC3 cells indicated that a xanthone named isobractatin (1) exhibited potent antiproliferative activity against the above three human cancer cell lines with IC₅₀ values ranging from 2.90 to 4.15 μM. Treatment of PC3 cells with 1 led to an enhancement of the cell apoptosis, and arrested cell cycle in the G0/G1 phase. The G0/G1 phase cycle-related proteins analysis showed that the expressions of cyclins D1 and E were reduced by 1, whereas the protein level of cyclin dependent kinase (CDK) inhibitor P21 was induced. Additionally, 1 enhanced PC3 cell apoptosis by activations of Bax, caspases 3 and 9, and by inhibition of Bcl-2. Our combined data illustrated that isobractatin (1) was the antiproliferative ingredient of G. bracteata against three human cancer cell lines, which exerted its antiproliferatrive effect via cell cycle arrest and induction of apoptosis.     

The lipophilic extract of Hypericum perforatum exerts significant cytotoxic activity against T24 and NBT-II urinary bladder tumor cells

Hypericum perforatum L. (St. John's wort) is a medicinal plant used for many pathologies, especially for the treatment of mild to moderate depression. In the present study we have investigated the cytotoxic activity of the locally collected (Epirus region) Hypericum perforatum L. against cultured T24 and NBT-II bladder cancer cell lines. The lipophilic extract of the herb, prepared using petroleum ether, induced apoptosis displaying LC(50) values at concentrations as low as 4 and 5 microg/mL. A fraction of this extract displayed 60 % cell growth inhibition at a concentration of 0.95 microg/mL. Evaluating the importance of various biologically active components of the extract, it was found that hypericins (hypericin, pseudohypericin, etc.) were identified only in the methanolic (lipophobic) extract of the herb, and not in the active lipophilic extract. In addition, hyperforin concentrations in the lipophilic extract and its most active fraction, were 0.94 microg/mL, and 0.17 microg/mL, respectively, while the active cytotoxic concentration of pure hyperforin appeared in the range of 1.8 microg/mL - 5.0 microg/mL. Therefore, pure hyperforin does not seem to contribute significantly to the cytotoxicity activity. Chlorophylls were identified in low, not significantly different, concentrations in all extracts and fractions and were not correlated to the biological activity. Owing to the combination of significant cytotoxic activity, natural abundance and low toxicity, the lipophilic extract of Hypericum perforatum holds the promise of being an interesting, new, antiproliferative agent against bladder cancer that deserves further investigation.     

牛蒡子浸膏的稳定性研究

目的确定牛蒡子浸膏的干燥条件。方法在不同的干燥温度和时间下,测定牛蒡子浸膏中有效成分牛蒡苷的含量。结果在80℃干燥48h后,牛蒡子浸膏有效成分牛蒡苷的损失较小,而在100℃烘48h后牛蒡苷的含量约下降了20．00％。结论牛蒡子浸膏的干燥温度应控制在80℃以下。     

Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays

A series of substituted 2-(aminopyridyl)- and 2-(aminopyrimidinyl)thiazole-5-carboxamides was identified as potent Src/Abl kinase inhibitors with excellent antiproliferative activity against hematological and solid tumor cell lines. Compound 13 was orally active in a K562 xenograft model of chronic myelogenous leukemia (CML), demonstrating complete tumor regressions and low toxicity at multiple dose levels. On the basis of its robust in vivo activity and favorable pharmacokinetic profile, 13 was selected for additional characterization for oncology indications.     

Pharmacognostic standardisation and antiproliferative activity of Aegle marmelos (L.) Correa leaves in various human cancer cell lines

Therapeutic management of cancer is a great clinical challenge and alternative medicines are being extensively explored to have integrated approach to cure cancer. Aegle marmelos (L.) Correa (Rutaceae) is known for its hypoglycaemic, radioprotective, antidiarrhoeal and many other pharmacological activities. The present study is designed to carryout pharmacognostic standardisation and evaluation of antiproliferative activity of the leaf extracts Aegle marmelos (L.) Correa (Rutaceae) and the chromatographic fractions of the most active extract. Hexane, petroleum ether, chloroform and ethanol extracts of the shade dried leaves were prepared by soxhelation and antiproliferative activity was assessed using human cancer cell lines of lung (A-549), colon (CoLo-05), ovary (IGR-OV-1), prostrate (PC3), leukaemia (THP-1) and breast (MCF-7) cancer. Bioactivity-derived fractionation was carried out for most active extract by column chromatography. The phytochemical studies indicated alkaloids, anthraquinones, terpenoids in the alcohol, chloroform extracts and tannins, terpenoids, reducing sugars in the petroleum ether and hexane extracts. Ethanol extract showed maximum inhibition in colon and breast carcinoma cell lines at a dose of 100 μg/ml. Column chromatography of the ethanol extract yielded five fractions. Out of this, fractions 2, 4 and 5 showed significant inhibition in leukaemia cell line with IC₅₀ of 12.5, 86.2 and >100 μg/ml for fractions 2, 4 and 5, respectively. High-performance thin layer chromatography of the fraction 2 revealed imperatorin as one of the major phytoconstituents. Among the different extracts investigated, ethanol extract exhibited significant antiproliferative activity and its fraction 2 containing furanocoumarin imperatorin showed antiproliferative activity against leukaemia cell line with IC₅₀ of 12.5 μg/ml.     

Design and synthesis of 2-iminothiazolidin-4-one moiety-containing compounds as potent antiproliferative agents

A new series of 2,5‐diaryliminothiazolidin‐4‐ones were designed and synthesized as potent antiproliferative agents. The antiproliferative activities of the 25 target compounds were evaluated against three cancer cell lines (A549, H460 and HT29) by MTT assay. Pharmacological data indicated that most of the compounds possessed moderate activity, some showed remarkable activity against one or more cell lines. As the most promising compound, 8s (with IC₅₀ values of 1.1, 0.01 and 1.3 µM against the A549, H460 and HT29 cell lines) was 1.1‐ to 270‐fold more potent than the reference drug sorafenib. Furthermore, preliminary structure–activity relationships (SARs) were summarized to provide guidance for further design and discovery of 2‐iminothiazolidin‐4‐one‐based antiproliferative agents.     

5-氟尿嘧啶衍生物的合成与抗肿瘤活性研究

目的寻找新型、高效的5-氟尿嘧啶衍生物类抗肿瘤化合物。方法设计、合成4个5-氟尿嘧啶衍生物,利用MTT方法测定这些化合物对4株肿瘤细胞的增殖抑制活性。结果 4个5-氟尿嘧啶衍生物均显示了较好的肿瘤细胞增殖抑制活性。结论 4个目标化合物对肿瘤细胞有较好的抑制活性,值得进一步研究。     

Jacaranone: A cytotoxic constituent from<Emphasis Type="Italic">senecio ambiguus</Emphasis> subsp.<Emphasis Type="Italic">ambiguus</Emphasis> (Biv.) DC. Against renal adenocarcinoma achn and prostate carcinoma LNCaP cells

Senecio ambiguus subsp. ambiguus (Biv.) DC. extracts were able to inhibit the in vitro proliferation of renal cell adenocarcinoma ACHN and hormone dependent prostate carcinoma LNCaP. The potential cytotoxic property of the plant was revealed by the methanolic extract action against LNCaP (IC50 of 5.51 microg/mL) and ACHN (IC50 of 38.95 microg/mL). The most potent cytotoxic activity (IC50 of 5.34 microg/mL against the prostate carcinoma cell line) was exerted by the dichloromethane extract. Through bioassay-guided fractionation of the dichloromethane extract jacaranone was isolated as the major active constituent. This quinoid showed a very strong activity against ACHN and LNcaP with IC50 of 4.32 and 7.39 microg/mL, respectively. Its structure was established by GC/MS and NMR analysis. The n-hexane extract showed an interesting inhibition on the proliferation of tumor cell lines an IC50 value of 5.23 microg/mL against LNCaP. Three compounds identified in the n-hexane extract such as nerolidol, a-humulene and g-tocopherol were found to be active aginst LNCAP with IC50 values ranged from 11.24 to 15.56 microg/mL.     

Design, synthesis, and antiproliferative activity of 3,4-diarylpyrazole-1-carboxamide derivatives against melanoma cell line

Synthesis of a new series of 3,4-diarylpyrazole-1-carboxamide derivatives is described. Their antiproliferative activity against A375P human melanoma cell line was tested and the effect of substituents on the diarylpyrazole scaffold was investigated. The biological results indicated that five synthesized compounds (Ig, Ii, IIc, IIg, and IIh) exhibited similar activity to Sorafenib. In addition, three compounds (IIa, IIb, and IIi) were more potent than Sorafenib. Among all of these derivatives, compound IIa which has dimethylamino and phenolic moieties showed the most potent antiproliferative activity against A375P human melanoma cell line. Virtual screening was carried out through docking of the most potent compound IIa into the domain of V600E-b-Raf and the binding mode was studied.     

Activity-guided fractionation of green tea extract with antiproliferative activity against human stomach cancer cells

Epidemiological studies have suggested that the consumption of green tea provides protection against stomach cancer. Fractionation of green tea extract, guided by antiproliferative activity against human stomach cancer (MK-1) cells, has resulted in the isolation of six active flavan-3-ols, epicatechin (EC), epigallocatechin (EGC), epigallocatechin gallate (EGCg), gallocatechin (GC), epicatechin gallate (ECg), gallocatechin gallate (GCg), together with inactive glycosides of kaempferol and quercetin. Among the six active flavan-3-ols, EGCg and GCg showed the highest activity, EGC, GC, ECg followed next, and the activity of EC was lowest. These data suggest that the presence of the three adjacent hydroxyl groups (pyrogallol or galloyl group) in the molecule would be a key factor for enhancing the activity. Since reactive oxygen species play an important role in cell death induction, radical scavenging activity was evaluated using the DPPH (1,1-diphenyl-2-picrylhydrazyl) radical. The order of scavenging activity was ECg > or = EGCg > or = EGC > or = GC > or = EC. The compounds having a galloyl moiety showed more potent activity. The contribution of the pyrogallol moiety in the B-ring to the scavenging activity seemed to be less than that of the galloyl moiety.     

Cytotoxicity and apoptotic inducibility of Vitex agnus-castus fruit extract in cultured human normal and cancer cells and effect on growth

A crude extract was prepared with ethanol from dried ripened Vitex agnus-castus fruits growing in Israel (Vitex extract). Cytotoxicity of the extract against human uterine cervical canal fibroblast (HCF), human embryo fibroblast (HE-21), ovarian cancer (MCF-7), cervical carcinoma (SKG-3a), breast carcinoma (SKOV-3), gastric signet ring carcinoma (KATO-III), colon carcinoma (COLO 201), and small cell lung carcinoma (Lu-134-A-H) cells was examined. After culture for 24 h (logarithmic growth phase) or 72 h (stationary growth phase), the cells were treated with various concentrations of Vitex extract. In both growth phases, higher growth activity of cells and more cytotoxic activity of Vitex extract were seen. The cytotoxic activity against stationary growth-phase cells was less than that against logarithmic growth-phase cells. DNA fragmentation of Vitex extract-treated cells was seen in SKOV-3, KATO-III, COLO 201, and Lu-134-A-H cells. The DNA fragmentation in Vitex extract-treated KATO-III cells was inhibited by the presence of the antioxidative reagent pyrrolidine dithiocarbamate or N-acetyl-L-cysteine (NAC). Western blotting analysis showed that in Vitex extract-treated KATO-III cells, the presence of NAC also inhibited the expression of heme oxygenase-1 and the active forms of caspases-3, -8 and -9. It is concluded that the cytotoxic activity of Vitex extract may be attributed to the effect on cell growth, that cell death occurs through apoptosis, and that this apoptotic cell death may be attributed to increased intracellular oxidation by Vitex extract treatment.     

Design,Synthesis, and Biological Evaluation of Pyrazole Derivatives

In this in vitro study, a series of novel pyrazole derivatives were designed, synthesized, and evaluated against five human cancer cell lines (PC3, A549, HL60, HCT116, and SW620) for their antiproliferative and p53‐MDM2 binding inhibitory activities. Although biological evaluations showed that this series of compounds possessed weak p53‐MDM2 inhibitory activities, most of them displayed moderate to potent antiproliferative activities against the tested cells lines. Compound 11c exhibited the best potency for MDM2 (FP‐IC₅₀ = 29.22 μm ) and demonstrated antiproliferative activities in response to the five tested cell lines (IC₅₀ = 4.09–16.82 μm ). Compared with the positive control Nutlin‐1, there was enhanced antiproliferative activity to p53‐mutated or p53‐deficient cell lines (SW620, HL60, and PC3).