Cytotoxicity of a novel biphenolic compound,bis(2-hydroxy-3-tert-butyl-5-methylphenyl)methane against human tumor cellsin vitro

Phenolic compounds are prevalent as toxins or environmental pollutants, but they are also widely used as drugs for various purpose including anticancer agent. A novel biphenolic compound, bis(2-hydroxy-3-tert-butyl-5-methylphenyl)methane (GERI-BP002-A) was isolated from the fermentation broth ofAspergillus fumigatus F93 previously, and it has revealed cytotoxicity against human solid tumor cells. Its effective doses that cause 50% inhibition of cell growthin vitro against non-small cell lung cancer cell A549, ovarian cancer cell SK-OV-3, skin cancer cell SK-MEL-2 and central nerve system cancer cell XF498 were 8.24, 10.60, 8.83, 9.85 μg/ml respectively. GERI-BP002-A has also revealed cytotoxicity against P-glycoprotein-expressed human colon cancer cell HCT15 and its multidrug-resistant subline HCT15/CL02, and its cytotoxicity was not affected by P-glycoprotein. We have also tested cytotoxicities of structurally related compounds of GERI-BP002-A such as diphenylmethane, 1,1-bis(3,4-dimethylphenyl)ethane, 2,2-diphenylpropane, 2-benzylpyridine, 3-benzylpyridine, 4,4′-di-tert-butylphenyl, bibenzyl, 2,2′-dimethylbibenzyl,cis-stilbene,trans-stilbene, 3-tert-butyl-4-hydroxy-5-methylphenylsulfide, sulfadiazine and sulfisomidine for studying of structure and activity relationship, and from these data we could suppose that hydroxyl group of GERI-BP002-A conducted important role in its cytotoxicity.     

Cytotoxic effects of pyridino[2,3-f]indole-4,9-diones on human tumor cell lines

The cytotoxicities of pyridino[2,3-f]indole-4,9-dione derivatives were examined against human lung tumor cell lines (A 549), human ovarian tumor cell lines (SK-OV-3), human melanoma tumor cell lines (SK-MEL-2), human CNS tumor cell lines (XF 498) and human colon tumor cell lines (HCT 15) in vitro using a Sulforhodamine B assay. 3-Ethoxycarbonyl-1-(2-methoxyethyl)-2-methyl-1H-pyridino[2,3-f]ind ole-4,9-dione (5) showed excellent cytotoxicity against XF 498 and HCT 15. The ED50 values of 5 were 0.006 microg/ml against XF 498 and 0.073 microg/ml against HCT 15, while those of doxorubicin were 0.012 and 0.264 microg/ml, respectively. 1-Benzyl-3-ethoxycarbonyl-2-methyl-1H-pyridino[2,3-f]indole-4,9-di one (7) (ED50 value 0.065 microg/ml) was also significantly more cytotoxic against HCT 15 compared with doxorubicin.     

Cytotoxic constituents ofPilea mongolica

Bioassay-guided fractionation of the aerial parts ofPilea mongolica (Urticaceae) afforded two cytotoxic triterpenoids, epi-oleanolic acid (I) and oxo-oleanolic acid (II). The structures of the compounds were confirmed by spectral and synthetic evidences. CompoundI and compoundII exhibited cytotoxicity against cultured human tumor cell lines, A549 (non small cell lung adenocarcinoma), SK-OV-3 (ovarian), SK-MEL-2 (skin melanoma), XF498 (CNS) and HCT15 (colon) with ED(50) values of 3.2 approximately 8.1 mug/ml and 0.7 approximately 6.8 mug/ml, respectively.     

Cytotoxic constituents ofSorbaria sorbifolia var.stellipila

The acivity-guided fractionation upon the MeOH extract of the aerial parts ofSorbaria sorbifolia var.stellipila led to the isolation of two cucurbitacin-compounds, cucurbitacin D and cucurbitacin F, as active principles. Two compounds were shown to exhibit significant cytotoxicity against cultured human tumor cell lines, A-549, SK-OV-3, SK-MEL-2, XF-498, and HCT 15.     

Synthesis of benzo[c]phenanthridine derivatives and theirin vitro antitumor activities

Aiming at the development of anticancer agents by modification of phenolic benzo[c]phenanthridine alkaloid, additional hydroxyl group was put on C10 position of fagaridine (1) by a biomimetic synthetic procedure to afford 10-hydroxyfagaridine (12). All of the synthetic intermediates were also screenedin vitro antitumor activities against five different cell lines as well as12. Among them the representative cytotoxic results are shown as follows;p-quinone (11) [ED₅₀ (A549=0.22 μg/ml), (HCT15=0.21 μg/ml), fagaridine (1) (HCT 15=0.41 μg/ml), olefin (6) (HCT 15=0.06 μg/ml), acetal (7) (SKMEL-2=0.07 μg/ml), dihydrofagaridne (10) (A549=0. 38 μg/ml), 10-hydroxyfagaridine (12) (A 549=0.45 μg/ml). From these observation three main remarks can be drawn; (i) the iminium part of benzo[c]phenanthridine is not essential for showing acitvities, (ii) the additional hydroxyl group did not contribute to enhance the cytotoxicity, (iii) the 3-arylisoquinolin-1(2H)-one derivatives were found to display significantin vitro antitumor activity.     

New cytotoxic sulfated saponins from the starfishCertonardoa semiregularis

Two new sulfated saponins designated as certonardosides P2 and I3 (1 and 2) were isolated from the brine shrimp active fraction of the MeOH extract of the starfish Certonardoa semiregularis. The structures were determined on the basis of spectral analysis. Compounds 1 and 2 were tested for cytotoxicity against five human tumor cell lines (A549, SK-OV-3, SK-MEL-2, XF498, and HCT15), and compound 1 displayed significant cytotoxicity against the SK-MEL-2 skin cancer cell.     

Cytotoxic constituents ofSaussurea lappa

The crude extract ofSaussurea lappa displayed significant lethality to brine shrimp larvae. Investigation of the causative components by bioactivity-directed fractionation resulted in the isolation of three C₁₇-polyene alcohols. Based on various nmr spectral data, these compounds were idenfitied as shikokiols which had been previously isolated fromCirsium nipponicum and/orCentaurea aegyptica. These C₁₇-polyene alcohols exhibited moderate cytotoxicities against the human tumor cell lines, A549, SK-OV-3, SK-MEL-2, XF498, and HCT15.     

Cytotoxic isoquinoline alkaloids from the aerial parts ofCorydalis incisa

Three known isoquinoline alkaloids were isolated from the chloroform-soluble fraction of the methanolic extract of the aerial parts of Corydalis incisa (Papaveraceae) through repeated column chromatography. Their chemical structures were elucidated as corynoline (1), corynoloxine (2) and 6-oxocorynoline (3) using spectroscopic analysis. Compounds 1-3 exhibited cytotoxicity against human A549, SK-OV-3, SK-MEL-2 and HCT15 tumor cells.     

Cytotoxic components from the dried rhizomes of Zingiber officinaleRoscoe

Five compounds were isolated from the chloroform-soluble fraction of the methanolic extract of the dried rhizomes of Zingiber officinale (Zingiberaceae) through repeated column chromatography. Their chemical structures were elucidated as 4-, 6-, 8-, and 10-gingerols, and 6-shogaol using spectroscopic analysis. Among the five isolated compounds, 6-shogaol exhibited the most potent cytotoxicity against human A549, SK-OV-3, SK-MEL-2, and HCT15 tumor cells. 6-shogaol inhibited proliferation of the transgenic mouse ovarian cancer cell lines, C1 (genotype: p53^-/-, c-myc, K-ras) and C2 (genotype: p53^-/-, c-myc, Akt), with ED₅₀ values of 0.58 μM (C1) and 10.7 μM (C2).     

A new cytotoxic acyclic diterpene fromCarpesium divaricatum

A new acyclic diterpene (1) and a known acyclic diterpene, 12(S)-hydroxygeranylgeraniol (2) were isolated from the aerial parts of Carpesium divaricatum. The structure of 1 was determined to be (2E,10E)-1,12-dihydroxy-18-acetoxy-3,7,15-trimethylhexadeca- 2,10,14-triene (1) on the basis of spectroscopic studies. Compounds 1 and 2 exhibited cytotoxicity against cultured human tumor cell lines, A549, SK-OV-3, SK-MEL-2, XF498, and HCT15, with ED50 values ranging from 4.3-10.2 micrograms/ml and 4.1-8.3 micrograms/ml, respectively.     

Cytotoxic effects of triterpenoid saponins from <Emphasis Type="Italic">Androsace umbellata</Emphasis> against multidrug resistance (MDR) and non-MDR cells

Cytotoxicity-guided fractionation and separation of MeOH extract from Androsace umbellata (Lour.) Merr. led to the isolation of four triterpenoid saponins. Compounds isolated from the n-BuOH soluble fraction were identified as saxifragifolin C (1), A (2), B (3), and D (4) by spectroscopic analysis. Antiproliferative effect of isolated compounds were evaluated by the sulforhodamin B assay against multidrug resistance (MDR; MES-SA/DX5 and HCT15/CLO2) and non-MDR (A549, SK-OV-3, SK-MEL-2, MES-SA, and HCT15) human tumor cell lines. All compounds exhibited strong cytotoxicity against non-MDR human tumor cell lines with IC₅₀ values of 0.19–2.37 μM. MDR cells and non-MDR cells had similar sensitivity to these compounds, however, MDR cells were highly resistant to doxorubicin. Compounds 1–4 induced an increase in the percentage of Annexin V-binding cells, indicating that 1–4 induced apoptosis in RAW 264.7 cells. Also, the condensation of nuclei, a characteristic morphological change of apoptosis, was observed in RAW 264.7 cells by the treatment with n-BuOH fraction, compounds 3 and 4, respectively.     

Phytochemical constituents of Artemisia stolonifera

Repeated column chromatographic separation of the CH2Cl2 extract of Artemisia stolonifera (Asteraceae) led to the isolation of a triterpene (I), a sesquiterpene (II), two aromatic compounds (III and IV) and a benzoquinone (V). Their structures were determined by spectroscopic means to be simiarenol (I), (1S,7S)-1beta-hydroxygermacra-4(15),5,10(14)-triene (II), 3'-methoxy-4'-hydroxy-trans-cinnamaldehyde (III), vanillin (IV) and 2,6-dimethoxy-1,4-benzoquinone (V), respectively. Among these products, compound V showed significant cytotoxicity against five human tumor cell lines in vitro, A549 (non small cell lung adenocarcinoma), SK-OV-3 (ovarian), SK-MEL-2 (skin melanoma), XF498 (CNS) and HCT15 (colon) with ED50 values ranging from 1.33-4.22 microg/ml.     

Guaiane sesquiterpenoids fromTorilis japonica and their cytotoxic effects on human cancer cell lines

A new compound 2 and two known guaiane-type sesquiterpenoids were isolated from the methylene chloride-soluble fraction of the methanolic extract of the fruits of Torilis japonica (Umbelliferae) through repeated silica gel and Sephadex LH-20 column chromatography. Their chemical structures were elucidated as torilin (1), 11-acetoxy-8-angeloyloxy-1beta-hydroxy-4-guaien-3-one (1beta-hydroxytorilin, 2), and 11-acetoxy-8-angeloyloxy-1alpha-hydroxy-4-guaien-3-one (1alpha-hydroxytorilin, 3) by spectroscopic analysis. Compounds 1-3 exhibited cytotoxicity against human A549, SK-OV-3, SK-MEL-2, and HCT15 tumor cells.     

Antitumor triterpenes from medicinal plants

Thirteen kinds of naturally occurring or derivatised triterpenes, reported to have an antitumoral property, were reinvestigated on the basis of their direct cytotoxicity or the inhibitory activity on cell growth against five kinds of cultured human tumor cells,i. e., A-549, SK-OV-3, SK-MEL-2, XF498 and HCT15,in vitro. Ursonic acidIII, betulinic acidVIII, betulonic acidX and glycyrrhetinic acidXI were exhibited a marked inhibition on cell growth.     

Cytotoxic activities of 6-arylamino-7-halo-5,8-quinolinediones against human tumor cell lines

6-Arylamino-7-halo-5,8-quinolinediones (4a-4k, 5a-5b) were tested for in vitro cytotoxicity against human solid tumor cell lines such as A 549 (non-small cell lung), SK-OV-3 (ovarian), SK-MEL-2 (melanoma), HCT-15 (colon) and XF 498 (CNS) by SRB assay. The arylamino-7-chloro-5,8-quinolinediones 4 were also evaluated for cyclin-dependent kinase (CDK2 and CDK4) inhibitory effect. Among them, the 5,8-quinolinediones 4a and 5a with 7-(4-fluorophenyl)amino group were found to be potent cytotoxic against HCT 15, SKOV-3 and XF 498, and the compounds 4f and 4i showed inhibitory activities for the CDK4.     

Sesquiterpene lactones from Carpesium rosulatum with potential cytotoxicity against five human cancer cell lines

In search for plant-derived cytotoxicity compound against human cancer cells (A549, SK-OV-3, SK-MEL-2, XF498, HCT15), it was found that the chloroform extracts obtained from the whole plant of Carpesium rosulatum MlQ. (Compositae) exhibited significant cytotoxic activity. Four sesquiterpene lactone, CRC1 (2α, 5-epoxy-5,10-dihydroxy-6-angeloyl-oxy-9β-isobutyloxy-germacran-8α,12-olide), CRC2 (2α,5-epoxy-5,10-dihydroxy-6α,9β-diangeloyloxy-germacran-8α,12-olide), CRC3 (2α,5-epoxy-5,10-dihydroxy-6α-angeloyloxy-9β-(3-methyl-butanoyloxy)-gemacran-8α,12-olide), CRC4 (2β,5-epoxy-5,10-dihydroxy-6α,9β-diangeloyloxy-germacran-8α,12-olide) were isolated from the whole parts of C. rosulatum. 2α,5-epoxy-5,10-dihydroxy-6α,9β-diangeloyloxy-germacran-8α,12-olide (CRC2) showed the most potent cytotoxicity with IC(50) value of 6.01 μM against SK-MEL-2.     

Cytotoxic constituents of <Emphasis Type="Italic">Amanita subjunquillea</Emphasis>

As part of our systematic study of Korean toxic mushrooms, we have investigated the constituents of Amanita subjunquillea. The column chromatographic separation of the MeOH extract of A. subjunquillea led to the isolation of four ergosterols, two cerebrosides and four cyclopeptides. Their structures were determined by spectroscopic methods to be (22E,24R)-5alpha,8alpha-epidioxyergosta-6,9,22-triene-3beta-ol (1), (22E,24R)-5alpha,8alpha-epidioxyergosta-6,22-dien-3beta-ol (2), (22E,24R)-5alpha,6alpha-epoxyergosta-8,22-diene-3beta,7beta-diol (3), (24S)-ergost-7-en-3beta-ol (4), 8,9-dihydrosoyacerebroside I (5), soyacerebroside I (6), beta-amanitin (7), phalloin (8), alpha-amanitin (9), and phalloidin (10). The compounds 1-6 and 8 were isolated for the first time from this mushroom. The isolated compounds were evaluated for the cytotoxicity against A549, SK-OV-3, SK-MEL-2 and HCT15 cells. Compound 9 exhibited significant cytotoxic activity against A549, SK-OV-3, SK-MEL-2 and HCT15 with ED(50) values of 1.47, 0.26, 1.57 and 1.32 microM, respectively.     

Cytotoxic germacranolide sesquiterpenes from the bark of <Emphasis Type="Italic">Magnolia kobus</Emphasis>

A new (3) and three known germacrane-type sesquiterpenoids were isolated from the chloroform-soluble fraction of the methanolic extract of the bark of Magnolia kobus (Magnoliaceae) through repeated silica gel and Sephadex LH-20 column chromatography. Their chemical structures were elucidated as costunolide (1), parthenolide (2), isobisparthenolidine (3), and bisparthenolidine (4) by spectroscopic analysis. Compounds 1–4 exhibited cytotoxicity against human A549, SK-OV-3, SK-MEL-2, and HCT15 tumor cells.     

Novel benzoylurea derivatives as potential antitumor agents; synthesis,activities and structure-activity relationships

A series of pyrazoloxyphenyl benzoyl urea derivatives was designed and synthesized for cytotoxic evaluation as potential antitumor agents. The synthetic compounds were evaluated for in vitro cytotoxicity against five human tumor cell lines, including A-549, SKOV-3, SK-MEL-2, XF-498 and HCT-15. Among others, compound 11 exhibited 50-100 times greater antitumor activities than the commercial product, Cisplatin.     

Antitumor activity ofTrichosanthes kirilowii

The activity-directed fractionation upon the MeOH extract of the root ofTrichosanthes kirilowii led to the isolation of eight cucurbitane triterpenes namely cucurbitacin B (I), isocucurbitacin B (II), cucurbitacin D (III), isocucurbitacin D (IV), 3-epi-isocucurbitacin B (V), dihydrocucurbitacin B (VI), dihydroisocucurbitacin B (VII) and dihydrocucurbitacin E (VIII), as active principles. All isolates were shown to exhibit significant cytotoxicity against cultured human tumor cells, including A-549, SK-OV-3, SK-MEL-2, XF-498 and HCT 15, with an exceptionally high potency.