Planta Medica

Published by Georg Thieme Verlag
Online ISSN: 1439-0221
Publications
Article
In experiments on young (aged 3 months) and old (aged 26 months) rats, using some conditioned-reflex methods with punishment or positive reinforcement for active and passive avoidance (shuttle-box, step-down, step-through, and water maze), we studied the effects of the standardized extracts of Panax ginseng (G115), Ginkgo biloba (GK501) and their combination Gincosan (PHL-00701). The extracts were administered orally for 7 days before training at three increasing doses: 17, 50, and 150 mg/kg for G115; 10, 30, and 90 mg/kg for GK501; and 27, 80, and 240 mg/kg for PHL-00701. The two extracts and their combination improved the retention of learned behavior. This effect varied considerably with the extracts, with the dose and with the behavioral method used. The results suggest that the Panax ginseng G115 and the Ginkgo biloba GK501 extracts possess properties similar in every respect to those of nootropic drugs. The favorable effects on learning and memory of the combination of G115 plus GK501 and the other pharmacological activities inherent in the extracts characterize this combination, offered as Gincosan as a particularly promising drug in geriatric practice.
 
Structures of compounds 1–9.  
Article
Three new depsidones ( 1, 3, and 4), a new diaryl ether ( 5), and a new natural pyrone ( 9) (synthetically known), together with three known depsidones, nidulin ( 6), nornidulin ( 7), and 2-chlorounguinol ( 8), were isolated from the marine-derived fungus ASPERGILLUS UNGUIS CRI282-03. Aspergillusidone C ( 4) showed the most potent aromatase inhibitory activity with the IC (50) value of 0.74 µM, while depsidones 1, 3, 6- 8 inhibited aromatase with IC (50) values of 1.2-11.2 µM. It was found that the structural feature of depsidones, not their corresponding diaryl ether derivatives (e.g. 5), was important for aromatase inhibitory activity. Aspergillusidones A ( 1) and B ( 3) showed radical scavenging activity in the XXO assay with IC (50) values of 16.0 and < 15.6 µM, respectively. Compounds 1 and 3- 7 were mostly inactive or showed only weak cytotoxic activity against HuCCA-1, HepG2, A549, and MOLT-3 cancer cell lines.
 
Article
As part of our ongoing chemical investigation of biologically active metabolites from marine-derived fungi, four new polyphenols containing both phenolic bisabolane and diphenyl ether units, expansols C-F (1-4), and one new diphenyl ether derivative, 3-O-methyldiorcinol (5), as well as twelve known compounds (6-17), were isolated from Penicillium expansum 091006 endogenous with the mangrove plant Excoecaria agallocha (Euphorbiaceae). The structures of the new metabolites were determined on the basis of NMR and mass spectroscopy. Among them, expansols C (1) and E (3) exhibited weak cytotoxicity against the HL-60 cell lines with IC50 values of 18.2 and 20.8 µM, respectively. The results showed that diphenyl ether substituted phenolic bisabolanes with a Δ7 double bond in the side chain are slightly less cytotoxic to HL-60 cell lines than the 7-OH or 7-OCH3 derivatives.
 
Primers used for real-time PCR quantification 
Chemical structure of 6-(1,1dimethylallyl)naringenin. 
Uterine wet weight following treatment of ovariectomized animals: uteri of (OvEx) ovariectomized control animals treated with carrier castor oil, (OvEx+E2) ovariectomized animals treated with 10 mg/ kg/d BW estradiol and (OvEx+ 6-DMAN) ovariectomized animals treated with 6-(1,1-dimethylallyl)naringenin at a concentration of 1.5 mg/ kg/d, 7.5 mg/kg/d and 15 mg/kg/d BW. 
Real-time RT-PCR analysis of uterine gene expression. Expression of progesterone receptor mRNA was analyzed by quantitative real-time RT-PCR analysis. Data of uterine gene expression of untreated ovariectomized control (OvEx), ovariectomized animals treated with 10 mg/kg/d BW estradiol (OvEx+E2) and ovariectomized animals treated with 6-(1,1-dimethylallyl)naringenin at a concentration of 1.5 mg/kg/d, 7.5 mg/kg/d and 15 mg/kg/d BW (OvEx+ 6-DMAN). The criterion for significance (*) was set at p £ 0.05. 
Article
Phytoestrogens are discussed as candidate substances to treat symptoms related to estrogen deficiency. In in vitro experiments, the naturally occurring flavonoid 6-(1,1-dimethylallyl)naringenin (6-DMAN) emerged as one of the most potent phytoestrogenic substances. 6-DMAN is not as well characterized as other flavonoids (8-prenylnaringenin) or isoflavones (genistein). We tested 6-DMAN for the first time in vivo, in a dose-dependent three-day uterotropic assay in ovariectomized Wistar rats, using 6-DMAN at three different concentrations (1.5 mg/kg; 7.5 mg/kg and 15 mg/kg BW/d). Estradiol (E2; 10 microg/kg BW/d) and the carrier castor oil were used as positive and negative controls. 6-DMAN did not have any effect on uterine wet weight, while the positive control E2 did. In contrast, 6-DMAN stimulated uterine mRNA expression of estrogen responsive genes in ovariectomized rats. Estrogen receptor alpha and beta mRNA were expressed in the uterus. They mediate the expression of genes with an estrogen responsive element in the promoter, e. g., complement C3 and the progesterone receptor. Therefore, we analyzed the expression of the above-mentioned genes in three different concentrations. 6-DMAN up-regulated progesterone receptor and particularly complement C3 mRNA expression however, less pronounced than E2. In conclusion, we demonstrated for the first time estrogenic activities of 6-DMAN in vivo. Surprisingly, although 6-DMAN regulated estrogen responsive gene expression, there was no uterine wet weight gain. These findings make 6-DMAN a very interesting candidate substance for further characterization, as it potentially represents a naturally occurring selective estrogen receptor modulator.
 
Estrogen inducible yeast receptor assay. Estrogenic potential of 8-prenylnaringenin (a), 6-(1,1-dimethylallyl)naringenin (b) and naringenin (c) were tested in concentration dependent manner. Experimental conditions and treatment procedures are given in Materials and Methods. Abbreviations: E2 = 17-b-estradiol, 8-PN = 8-prenylnaringenin, 6DMAN = 6-(1,1-dimethylallyl)naringenin and Nar. = naringenin.
Estrogen inducible MVLN luciferase assay. Estrogenic potential of 8-prenylnaringenin (a), 6-(1,1-dimethylallyl)naringenin (b) and naringenin (c) were tested using different concentrations. Experimental conditions and treatment procedures are given in Materials and Methods. Abbreviations: E2 = 17-b-estradiol, 8-PN = 8-prenylnaringenin, 6-DMAN = 6-(1,1-dimethylallyl)naringenin, Nar. = naringenin and OHTam = 4-hydroxytamoxifen.
Chemical structures of the naringenin derivatives.  
Article
Chemically synthesized naringenin derivatives, identical to natural occurring compounds, were tested for their estrogenic activity using two independent estrogen screening assays. Using a yeast based estrogen receptor assay, strong estrogenic activities were demonstrated for 6-(1,1-dimethylallyl)naringenin and 8-prenylnaringenin, while the parent compound naringenin did not show recognizable estrogenic activity. In MVLN cells, a bioluminescent MCF-7-derived cell line, the estrogenic activity of 8-prenylnaringenin and 6-(1,1-dimethylallyl)naringenin was detected at concentrations of 10(-6) M and 5 x 10(-6) M respectively. Naringenin demonstrated estrogenic activity but only at a concentration of 10(-5) M. These estrogenic effects are mediated by the ER, as the antiestrogen 4-hydroxytamoxifen inhibited these activities. In summary, this study provides the further confirmation that 8-prenylnaringenin demonstrates high estrogenic activity, and demonstrated for the first time for 6-(1,1-dimethylallyl)naringenin a reasonable high estrogenic activity, while naringenin exhibit low or no estrogenic activity.
 
Chemical structures of the naringenin derivatives.  
PSA concentration in the supernatant of treated PC3(AR) 2 cells. Antiandrogenic potentials of 6-(1,1-dimethylallyl)naringenin, 8-prenyl- naringenin and naringenin were tested at concentrations of 10 ±5 M and compared to the effect of bicalutamide (10 ±5 M) and estradiol (10 ±8 M) with simultaneous dihydrotestosterone (10 ±6 M) treatment. Experimental conditions and treatment procedures are described in Materials and Methods.  
Androgen inducible yeast receptor assay. Antiandrogenic potentials of 6-(1,1-dimethylallyl)naringenin (a), 8-prenylnaringenin (b), and naringenin (c) were tested in a concentration-dependent manner in combination with 10 ±8 M dihydrotestosterone. Experimental conditions and treatment procedures are described in Materials and Meth- ods.  
Androgen inducible yeast receptor assay. Androgenic potentials of 8-prenylnaringenin, 6-(1,1-dimethylallyl)naringenin and naringenin were tested in a concentration-dependent manner. Experimental conditions and treatment procedures are described in Materials and Methods.  
Article
Naturally occurring naringenin derivatives, known for their estrogenic activity, were tested in two independent (anti-)androgen screening assays. Using a yeast-based androgen receptor assay relatively strong antiandrogen activities were demonstrated for 6-(1,1-dimethylallyl)naringenin and 8-prenylnaringenin, while the parent compound naringenin did not show recognizable antiandrogen activity. In an androgen receptor activity assay based on the analysis of prostate specific antigen (PSA) concentrations in the supernatants of treated PC3(AR)2 cells the antiandrogenic activity of 6-(1,1-dimethylallyl)naringenin was detected at concentrations of 10⁻⁵ M. 8-Prenylnaringenin or naringenin have no detectable antiandrogenic effect. In summary, for the first time we provide evidence of the antiandrogenic activity of 6-DMA-N in two independent model systems. In conclusion, we demonstrated the ability of prenylated naringenins not only to act via the estrogen receptor but also through the androgen receptor. Abbreviations DHT:dihydrotestosterone PSA:prostate-specific antigen Bic:bicalutamide 6-DMA-N:6-(1,1-dimethylallyl)naringenin 8-P-N:8-prenylnaringenin E2:17-β estradiol
 
Article
The aerial parts of MIKANIA MICRANTHA from a collection in Paraguay gave, in addition to mikanolide, deoxymikanolide, and miscandenin, five new germacranolides all derived from 14,15-dihydroxygermacra-1(10) E,4 Z-dien-12,8alpha-olide.
 
Article
A novel C18-polyacetylene, (+)-9( Z),17-octadecadiene-12,14-diyne-1,11,16-triol, has been isolated from the ethyl acetate extract of Cassonia barteri (Araliaceae) leaves collected in Cameroon. The structure determination was achieved by NMR, mass, IR, and UV spectroscopy. The new polyenyne shows antibacterial activity against Bacillus subtilis and Pseudomonas fluorescens, antifungal activity against Cladosporium cucumerinum, moiluscicidal activity against Biomphalaria glabrata at low concentrations, and in addition it possesses haemolytic activity.
 
Article
Among the quassinoids isolated from Eurycoma longifolia Jack, eurycomanone was identified as the most potent and toxic inhibitor of the chloroquine-resistant Gombak A isolate of Plasmodium falciparum. Several diacylated derivatives of eurycomanone, 1,15-di-O-isovaleryleurycomanone, 1,15-di-O-(3,3-dimethylacryloyl)- eurycomanone and 1,15-di-O-benzoyleurycomanone were synthesized by direct acylation with the respective acid chlorides. The monoacylated 15-O-isovaleryleurycomanone was synthesized by selective protection of the other hydroxy groups of eurycomanone with trimethylsilyl trifluoromethanesulphonate to enable the exclusive acylation of its C-15 hydroxy group. This was followed by the removal of the protecting groups with citric acid. The diacylated eurycomanones exhibited lower antiplasmodial activity against the Gombak A isolates and lower toxicity in the brine shrimp assay when compared to eurycomanone. In contrast, the monoacylated derivative displayed comparable antiplasmodial potency to eurycomanone, but its toxicity was reduced. Thus, preliminary studies of the synthesized acylated eurycomanones have shown that acylation only at the C-15 hydroxy group may be worthy of further antimalarial investigation.
 
Article
A new diterpenoid alkaloid was isolated from the overground parts of ACONITUM BARBATUM Pers. (Ranuncluaceae). Its structure was elucidated by spectroscopic methods as 11-acetyl-1,19-epoxydenudatine.
 
Article
A rapid isotachophoretic separation of benzo[ C]phenanthridine alkaloids from CHELIDONIUM MAJUS L. is described. The method allows the determination of sanguinarine and chelerythrine in the presence of other isoquinoline alkaloids in crude alkaloids extracts.
 
Article
Four new isoprenylated xanthones, cudraxanthones A, B and C were isolated from the N-hexane extract of the root bark of CUDRANIA TRICUSPIDATA (Carr.) Bur. (Japanese name "Hariguwa"; Moraceae), and cudraxanthone D from the benzene extract. The structures of cudraxanthones A, B, C and D were shown to be 1-4, respectively, on the basis of spectral and chemical evidence.
 
Article
Thirteen saponins have been isolated from the rhizomes of Panax pseudo-ginseng subsp. himalaicus and its var. bipinnatifidus. They were characterized by examining their hydrolysis products, spectral data, and direct comparison with authentic samples
 
Article
The synthesis of the potential acronycine prodrugs, 1-hydroxy-1,2-dihydroacronycine ( 2) and 2-hydroxy-1,2-dihydroacronycine ( 3) are described using the natural alkaloid acronycine ( 1) as starting material.
 
Article
Phloroglucinol triacetate and eight oligomers of phloroglucinol (phlorotannins) were isolated from a phenolic fraction of CYSTOSEIRA GRANULATA extracted by ethyl acetate. The structures were elucidated by spectroscopic methods using the acetyl derivates. In addition to the three known oligomers, diphlorethol acetate, bifuhalol acetate, triphlorethol-B-heptaacetate, five new substances were isolated: fucotriphlorethol-B-dodecaacetate, fucotetraphlorethol-A-tetradecaacetate, fucopentaphlorethol-A-hexadecaacetate, fucoheptaphlorethol-A-eicosaacetate and an unidentified 8-membered-ring compound.
 
Article
The flowers of ARNICA CHAMISSONIS ssp. GENUINA afforded in addition to 8 helenanolides ivalin, the first eudesmanolide found in the genus ARNICA.
 
Article
Sho-Saiko-To (SST) is a modified Japanese traditional Chinese herbal medicine containing seven medical plants: Bupleuri radix, Pinelliae tuber, Suxtallariae radix, Zizyphi fructus, Ginseng radix, Glycyrrhizae radix, and Zingiberis recens rhizoma. This preparation has been used in the treatment of some inflammatory diseases of the respiratory system and chronic hepatitis. In the present study, the effects of SST were investigated on the activities of DNA-synthesizing enzymes in 1,2-dimethylhydrazine (DMH)-induced colonic carcinomas in rats. Six-week administration of SST prevented nearly 100% of the body weight loss and the final number of the colonic carcinomas compared to those in the rats treated with DMH alone, and suppressed the enhanced activities of thymidylate synthetase (TS) and thymidine kinase (TK) which were involved in the de novo and salvage pathways of pyrimidine synthesis, respectively, in DMH-induced colonic carcinomas. These results indicate that SST may show directly and/or indirectly inhibitory effects on the development of colonic carcinomas.
 
Article
The bark of Taxus chinensis yielded a new taxane diterpenoid, 2-deacetoxy-7,9-dideacetyltaxinine J ( 1) together with several known taxoids. (1)H- and (13)C-NMR data of 1 are reported.
 
Article
The resin produced by COMMIPHORA INCISA has yielded two epimeric aryltetralin lignans which have been identified as the known polygamain (1 R, 2 R, 3 R) and its novel C-2 epimer to which the trivial name picropolygamain (1 R, 2 S, 3 R) has been assigned.
 
Article
A new isoprene substituted flavanone ( 1), named cudraflavanone A, was isolated from the root bark of CUDRANIA TRICUSPIDATA (Carr.) Bur. together with three known flavonoids, cycloartocarpesin ( 2), populnin ( 3), and quercimeritrin ( 4). The structure of 1 was determined on the basis of the spectral evidence and the total synthesis. The structure of euchrestaflavanone C ( 5) which had been isolated from EUCHRESTA JAPONICA Hook, f. ex Regel was also determined on the basis of the total synthesis.
 
Article
Four new isoprenylated xanthones, cudraxanthones L, M, N, and O were isolated from the ethanol extract of the root bark of CUDRANIA TRICUSPIDATA (Carr.) Bur. (Moraceae), collected in China. The structures of cudraxanthones L, M, N, and O were shown to be 1-4, respectively, on the basis of chemical and spectral evidences.
 
Article
Two new furo-1,2-naphthoquinones, crataequinones A (1) and B (2), were isolated from the fruits of Crataegus pinnatifida. The structures of two new compounds were determined as 11,12-dimethoxy-3,4-furo-1,2-naphthoquinone (1) and 11,12-dimethoxy-5-hydroxy-3,4-furo-1,2-naphthoquinone (2) by spectroscopic analysis. The two compounds 1 and 2 showed significant inhibitory activity with IC50 values of 33 and 90 microM, respectively, against the expression of intercellular adhesion molecule-1 (ICAM-1).
 
Article
Four new isoprenylated xanthones, cudraxanthone H,I,J, and K were isolated from the ethanol extract of the root bark of CUDRANIA TRICUSPIDATA (Carr.) Bur. (Moraceae), collected in China. The structures of cudraxanthones H,I,J, and K were shown to be 1- 4, respectively, on the basis of chemical and spectral evidence.
 
Article
The distributions of the alkaloids colchicine, 2-demethylcolchicine, 3-demethylcolchicine, demecolcine, 2-demethyldemecolcine, and 3-demethyldemecolcine in the corms, stems, leaves, flowers, and seeds of COLCHICUM CILICICUM were analysed by HPLC. In addition, the alkaloids cornigerine, N-formyl- N-deacetylcolchicine, N-methyl-demecolcine, beta-lumicolchicine, gamma-lumicolchicine, beta-lumidemecolcine, gamma-lumidemecolcine, and N-ethoxycarbonyldemecolcine were identified, the last named being reported for the first time from a COLCHICUM species. The flavones luteolin and apigenin were isolated and benzoic, 2-hydroxy-6-methoxybenzoic, and vanillic acids were also detected.
 
Affinity (pKi) for the aporphine alkaloids at human cloned a 1 -AR subtypes as determined by competition experiments 
Chemical structures of the tested compounds. 
Effects of aporphine alkaloids on PDE isolated from bovine aorta 
Article
We have studied the mechanism of action of three 6a(R)-1,2-methylenedioxyaporphines as vasorelaxant compounds. The alkaloids assayed showed different affinities for the three human cloned α1-adrenoceptor (AR) subtypes stably expressed in rat-1 fibroblasts, showing lower affinity for α 1B-AR with regard to the α 1A- or α 1D-subtypes. These three natural compounds are more potent inhibitors of [³H]-prazosin binding than of [³H]-diltiazem binding to rat cerebral cortical membranes. As all these alkaloids inhibited noradrenaline (NA)-induced [³H]-inositol phosphate formation in cerebral cortex and rat tail artery, they may be safely viewed as α1-AR antagonists, as is demonstrated by the vasorelaxant responses observed in isolated rat tail artery and/or aorta precontracted with NA. The alkaloids also inhibited the contractile response evoked by KCl (80 mM) but with a lower potency than that shown against NA-induced contraction. We have also examined their ability to inhibit the different forms of cyclic nucleotide phosphodiesterases (PDE) isolated from bovine aortic smooth muscle and endothelial cells, with negative results. We conclude that N-methylation favours the interaction of (R)-aporphines with all α1-AR subtypes, and that the topography of the binding site recognizing the basic or protonated nitrogen atom is similar in all three α1-AR subtypes. The presence of a hydroxy group at C-11 has different effects on the affinity for each α1-AR subtype but decreases the affinity for Ca²⁺ channels. These results confirm and extend the view that subtle changes in the hydroxylation patterns on the aromatic ring of the aporphine structure affect the interactions of these compounds with the three α1-AR subtypes in different ways, suggesting that the binding site recognizing the aporphine skeleton is different in each of the three subtypes. Abbreviations PDE:cyclic nucleotide phosphodiesterase AR:adrenoceptor NA:noradrenaline [¹²⁵I]-HEAT:[¹²⁵I]iodo-2[β-(4-hydroxyphenyl)-ethylamino-methyl]-tetralone
 
Article
The cytostatic potentials of 16 clavines were determined in the L5178y mouse lymphoma cell system: three of them are natural 8-hydroxymethylergoline type alkaloids (elymoclavine, lysergol, dihydrolysergol-I) and 13 are semisynthetic derivatives ( O-acyl-; 1-alkyl-; 1-alkyl- O-acyl-; 1, O-dialkyl-; masked aldehydes). It is shown that in contrast to these alkaloids some of their derivatives are potent cytostatic agents: 1-propylelymoclavine (ED (50) cone.: 2.2 microM), 1-propylelymoclavine- O-butyrate (2.7 microM), 6-methyl-8beta-(2'-oxo-cyclohexylidenemethyl)-ergoline-I (4.0 microM). O-Acyl derivatives without substitution at N-1 were almost inactive. The substitution of the hydrogen at N-1 of inactive clavines by an alkyl group with three carbon atoms led to very active compounds indicating that the nature of the substituent at N-1 is very important for cytostatic activity. Incorporation studies in the presence of 1-propylelymoclavine showed that this compound inhibits primarily DNA synthesis. Partial syntheses of new ergolines are described.
 
Article
A receptor binding assay directed separation has led to the identification of a minor alkaloid 6-methoxy- N-methyl-1,2, 3,4-tetrahydro-beta-carboline (1) from the Chinese herbal drug Evodiae Fructus [EF, the dried, unripe fruit of Evodia rutaecarpa Look. f. et Thomas (Rutaceae)]. The structure of compound 1 was elucidated by means of spectroscopic methods and a comparison with synthetic materials. Compound 1 interacted with 5-HT (1A) and 5-HT (2) receptors with a moderate K (i) value of 78 and 1.2 microM, respectively. Compound 1 is found in EF and the genus Evodiae for the first time.
 
Article
In this study, we investigated the hepatoprotective effects of four compounds from Galla Rhois [gallic acid methyl ester, gallic acid, an equilibrium mixture of 3-galloyl-gallic acid and 4-galloyl-gallic acid isomers, and 1,2,3,4,6-penta-O-galloyl-β-D-glucose (PGG)] in primary rat hepatocytes undergoing necrosis or apoptosis. Treatment with gallic acid methyl ester (12.5 and 50 μM) or PGG (3.125, 12.5 and 50 μM) reduced hepatocyte necrosis induced by tert-butyl hydroperoxide. PGG treatment (4 and 20 μM) also altered hepatocyte apoptosis induced by glycochenodeoxycholic acid. Based on these results, we propose that PGG warrants further evaluation as a hepatoprotective agent, because it protected primary rat hepatocytes from both necrosis and apoptosis. Abbreviations GA:gallic acid GAME:gallic acid methyl ester GCDC:glycochenodeoxycholic acid GGA:equilibrium mixture of 3-galloyl-gallic and 4-galloyl-gallic acids JNK:c-jun-NH2-terminal kinase LDH:lactate dehydrogenase PARP:poly(ADP-ribose) polymerase PGG:1,2,3,4,6-penta-O-galloyl-β-D-glucose tBH:tert-butyl hydroperoxide
 
Article
Many anti-inflammatory agents are known to significantly enhance the terminal differentiation of some cancer cells such as leukemia cells. In this study, the effect of yomogin, a eudesmane sesquiterpene lactone isolated from Artemisia princeps with anti-inflammatory activity, was investigated in human promyelocytic leukemia HL-60 cells. Yomogin by itself induced small increases in cell differentiation, with less than 19 % of the cells attaining a differentiated phenotype. Importantly, yomogin synergistically enhanced differentiation of HL-60 cells in a dose-dependent manner when combined with either 5 nM 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] or 50 nM all-trans retinoic acid (all-trans RA). Cytofluorometric analysis and morphologic studies indicated that the combinations of yomogin and 1,25-(OH)2D3 stimulated differentiation to monocytes whereas the combinations of yomogin and all-trans RA stimulated differentiation to granulocytes. These results suggest that yomogin may be useful in combination with 1,25-(OH)2D3 or all-trans-RA in the differentiation therapy for myeloid leukemias. Abbreviations 1,25-(OH)2D3:1,25-dihydroxyvitamin D3 FITC:fluorescein isothiocyanate NBT:nitroblue tetrazolium RA:retinoic acid PE:phytoerythrin
 
Article
From the cell walls of various Phytophthora species (Oomycetes) different water-soluble beta-1,3/1,6-glucans were isolated and characterized. The glucans with relative molecular masses between 13 and 50 kd exhibited varying degrees of branching in the beta-1,3-linked glucan backbone ranging from 14 to 50%. The dose-dependent antitumor activity of the glucans against allogeneic sarcoma-180 was investigated. It could be demonstrated that beta-1,3/1,6-glucans with relative molecular masses below 50 kd can exhibit a prominent antitumor activity (inhibition rate up to 99%), being comparable to that of the high relative molecular mass (450 kd) beta-1,3/1,6-glucans. Biological activity of the glucans could be shown to be correlated with a low degree of branching. The most potent glucan with a degree of branching of 14% also was active against the syngeneic DBA/2-MC.SC-1 fibrosarcoma (inhibition rate up to 90%) and in combination with a suboptimum dose of diethylstilbestrol against Nobel-Nb prostate carcinoma (inhibition rate up to 90%).
 
Article
Stem bark (covered with gum) of Acacia tortilis (Forsk.) Hayne subsp. raddiana (Savi) Brenan, used as a remedy against asthma in Somalia, contains two new pharmacologically active compounds named quracol A and B. Quracol A is 1-(2, 4-dihydroxyphenyl)-3-(3-hydroxyphenyl)-propan-2-ol. Quracol B is 1-(2,4-dihydroxyphenyl)-3-(3, 4-dihydroxyphenyl)-propan-2-ol. The compounds have very low optical activity. No optical activity can be determined for quracol A. 1H-NMR with chiral shift reagents does not indicate quracol A to be racemic. In a CD-experiment, [θ]290 = -807 is found for quracol B. Both substances inhibit electrically induced contractions of the isolated guinea pig ileum at concentrations in the bath of 20 µg/ml. Histamine-induced contractions are also inhibited.
 
Inhibitory capacity of the 1,3-b-D-glucan synthase activity by convolvulaceaous glycolipids of the tricolorin and orizabin series 
Article
Sixteen convolvulaceous glycolipids selected from the tricolorin (1 - 7) and orizabin (8 - 16) series, proved to be strong in vitro inhibitors of the enzyme that catalyzes the synthesis of 1,3-beta-D-glucan, a major polymer of fungal cell-walls. Results provide an insight into function of the specific structures of these complex macrocyclic lactones as inhibitors of the 1,3-beta-D-glucan synthase and open the possibility of using these compounds as starting points for the development of antifungal agents that act by inhibiting fungal cell-wall synthesis.
 
Article
(3R,6R)-4-methyl-6-(1-methylethyl)-3-phenylmethylperhydro-1,4-oxazine-2,5-dione (1) was isolated from the fruiting bodies of Isaria japonica as an apoptosis-inducing agent. The complete structural assignment of the compound was accomplished on the basis of spectroscopic methods and chemical transformations. Compound 1 induced apoptotic cell death of the human leukemia cells (HL-60) in a dose-dependent manner, ranging from 5.0 microg/ml to 100.0 microg/ml.
 
Article
New chalcone and dimeric chalcones with 1,4- P-benzoquinone residue, combrequinone A (1), combrequinone B (2), and combrequinone C (3), along with three known compounds (4-6), were isolated from the ethanolic extract of the stems and leaves of Combretum yunnanense, and their structures were determined by spectroscopic analysis. Compounds 1-3 were evaluated for in vitro cytotoxicity against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7, and SW480. Compounds 1, 2 and 3 were found to be most potent against HL-60 acute leukemia cells, with IC₅₀ values of 4.63, 4.07, and 1.26 µM, respectively.
 
Article
The antioxidant effects of 1,5-anhydro-D-fructose (1,5-AF), a unique anhydrohexulose, were studied in 1,1-diphenyl-2-picrylhydrazyl (DPPH) solution, in human cells along with lipid peroxidation of low-density lipoprotein (LDL). We have confirmed that 1,5-AF scavenges DPPH radicals directly in solution and inhibits the formation of hydrogen peroxide and superoxide anion, typical reactive oxygen species (ROS), induced by phorbol myristate acetate (PMA) in a dose-dependent manner in THP-1 cells. We also observed the dose-dependent antioxidant effects of 1,5-AF on copper-mediated LDL oxidation. These findings suggest that 1,5-AF might play a role in reducing the risk of atherosclerosis and may help prevent coronary heart disease.
 
Article
To gain more insights into structure-activity relationships, four 3',4'-dihydroxyflavonols differing in the substitution of the A and C rings and 1,5-dicaffeolyquinic acid were evaluated for their ability to inhibit chemiluminescence of human neutrophils stimulated with opsonized zymosan or FMLP as well as in an enzymatic system with H2O2 and horseradish peroxidase. It could be shown that an additional o-dihydroxy structure in the A-ring, or a 6-methoxy group, respectively, has no significant influence, thus confirming the o-dihydroxy group of the B-ring as the most important structural feature for the radical scavenger activity. It can be supposed that the main effect of the tested flavonols is based on their inhibition of myeloperoxidase, besides inhibition of enzymes involved in activating the NADPH-oxidase, and a direct reaction with oxygen radicals. Inhibition of chemiluminescence by 1,5-dicaffeoylquinic acid was in the same order as those observed with the flavonols.
 
Article
1,5-Anhydro-D-fructose (AF) was first found in fungi and red algae. It is produced by the degradation of glycogen, starch and maltosaccharides with α-1,4-glucan lyase (EC 4.2.2.13). In vivo, AF is metabolized to 1,5-anhydro-D-glucitol (AG), ascopyrone P (APP), microthecin and other derivatives via the anhydrofructose pathway. The genes coding for the enzymes in this pathway have been cloned, enabling the large-scale production of AF and related products in a cell-free reactor. The possible applications of these products in medicine have been evaluated using both in vitro and in vivo systems. Thus AF is a useful anticariogenic agent as it inhibits the growth of the oral pathogen Streptococcus mutans, impairing the production of plaque-forming polysaccharides and lactic acid. AF also shows anti-inflammatory and anticancer effects. AG is used as a diabetic marker for glycemic control. AG also stimulates insulin secretion in insulinoma cell lines. in vivo, APP has been shown to lengthen the life span of cancer-afflicted mice. It interferes with tumor growth and metastasis by its cidal effects on fast multiplying cells. Microthecin inhibits the growth of the human pathogen Pseudomonas aeruginosa PAO1, particularly under anaerobic conditions. The pharmaceutical usefulness of the other AF metabolites 1,5-anhydro-D-mannitol,1-deoxymannojirimycin, haliclonol, 5-epipentenomycin I, bissetone, palythazine, isopalythazine, and clavulazine remains to be investigated. In this review AF and its metabolites as the bioactive natural products for their pharmaceutical potentials are discussed.
 
Article
From the rhizomes of HYPOXIS OBTUSA two monoglucosides having the same aglycone as hypoxoside, 1-(3',4'- dihydroxyphenyl)-5-(3'',4''-dihydroxyphenyl)-1-pen-ten-4-yne, have been obtained. By methylation followed by hydrogenation they have been transformed into the same compound, 1-(3'-methoxy-4'- O-beta- D-glucopyranosyl-phenyl)-5-(3''-4''-dimethoxyphenyl)-pentane, likewise obtainable through partial hydrolysis of hypoxoside.
 
Article
From the latex of Synadenium grantii Hook F. (Euphorbiaceae) were isolated by chromatographic methods five diterpene 12,13-diesters of the tigliane-type parent alcohols 4-deoxyphorbol (1a), 4,20-dideoxy-5α-hydroxyphorbol (2a) and 20-deoxy-5α-hydroxyphorbol (3a) with isobutyric, tiglic and phenylacetic acid. Of these, 4-deoxyphorbol-13-(phenylacetate)-12-tiglate (1f) turned out to be highly irritant on the mouse ear while the rest of the esters had rather low or no irritant activity; 1f was also assayed for tumor-promoting activity and proved to be almost inactive.
 
Article
There is an increasing demand from both patients and practicing oncologists for orally formulated chemotherapy. The present study focused on the oral formulation for natural products that may be effectively used in oncologic treatment regimens. Tumor-bearing mice treated with intratumoral administration of aqueous ammonium oxalate-soluble and ethanol-insoluble derivatives of Agaricus blazei showed marked tumor regression at doses ranging from 0.1 to 2.5 mg (p < 0.05 vs. saline control; n = 7). However, oral administration of this same fraction, either prior to, simultaneously with, or after, tumor cell inoculation did not result in tumor regression (p > 0.05 vs. control). When this fraction was treated with hydrochloric acid (acid-treated fraction; ATF), intratumoral administration resulted in a marked regression of tumor growth comparable to that of the acid-untreated fraction. More importantly, parenteral administration of ATF resulted in a significantly greater regression of tumor growth than that produced by the untreated fraction (p < 0.05 vs. untreated; n = 7). When a total of 4.5 mg of ATF was given orally at varying schedules prior to, simultaneously with, or after, tumor inoculation, a significant regression was seen using a schedule starting 4 days prior to inoculation (p < 0.05 vs. all other treatments; n = 7). NMR and molecular analyses showed that the ATF fraction had a molecular weight of approximately 10 kDa and consisted mainly of only (1,6)-beta- D-polyglucose. These results suggest that the oral administration of simple acid-treated ATF results in a remarkable tumor regression. Thus, simple acid hydrolysis of natural products may not only bring measurable benefits in oncological practice, but may also be a useful general formulation for natural products for oral chemotherapy.
 
Article
We attempted to isolate lipolytic substances from the stem and rhizome of Sinomenium actum Rehder et Wilson by using high-performance liquid chromatography (HPLC). S-I and S-II were isolated from the fractions showing lipolytic activity. S-I and S-II were identified as caffeine and 1,7-dimethylxanthine, respectively, by direct comparison with authentic samples. Caffeine (S-I) dose-dependently stimulated lipolytic activity in isolated fat cells of rats, at concentrations of 500 to 1000 microM. 1,7-Dimethylxanthine (S-II) also stimulated lipolytic activity at concentrations of 500 to 1000 microM. Furthermore, we found that caffeine and 1,7-dimethylxanthine enhanced catecholamine-induced lipolysis at lower concentrations of 0.1 to 1 microM.
 
Article
1,8-cineole (cineole) and beta-pinene, two monoterpenes isolated from the essential oil obtained from Eucalyptus camaldulensis Dehn leaves were tested for antinociceptive properties. Tail-flick and hot-plate methods, reflecting the spinal and supraspinal levels, respectively, were used in mice and/or rats using morphine and naloxone for comparison. Cineole exhibited an antinociceptive activity comparable to that of morphine, in both algesic stimuli. A significant synergism between cineole and morphine was observed, but naloxone failed to antagonize the effect of cineole. Beta-pinene exerted supraspinal antinociceptive actions in rats only and it reversed the antinociceptive effect of morphine in a degree equivalent to naloxone, probably acting as a partial agonist through the mu opioid receptors. From structure-activity relationships of the pairs morphine+cineole and naloxone+beta-pinene, it was shown that similarities exist in the stereochemistry and in the respective atomic charges of these molecules. Further studies are in progress in order to elucidate the mechanism of action of the two terpenoids.
 
Article
The effects of the essential oil of Eucalyptus tereticornis Sm. (EOET) on guinea-pig tracheal smooth muscle were investigated. EOET (10 - 1000 microg/mL) relaxed the tracheal basal tonus with an EC (50) value of 125.3 [52.2 - 300.9] microg/mL. Its maximal relaxation (40 +/- 6 %) was significantly lower than that evoked by aminophylline (209 +/- 34 %). The K (+)-(60 mM)-induced contractions were significantly reduced by both EOET (200 - 1000 microg/mL) and its main constituent 1,8-cineole (600 - 1000 microg/mL). Acetylcholine (1 microgM)-induced contractions were significantly enhanced by 1,8-cineole (10 - 1000 microg/mL). However, they were significantly enhanced and reduced by lower (200 - 400 microg/mL) and higher (800 - 1000 microg/mL) concentrations of EOET, respectively. Electrical field stimulation-induced contractions were significantly increased by EOET (100 - 600 microg/mL). In conclusion, EOET produces myorelaxant effects on guinea-pig isolated trachea, an effect that seems to result from a complex interaction between its monoterpenoid constituents.
 
Article
One hour after the addition of 0.5 ml rosemary oil per cage for evaporation (141 of volume) the concentration of 1,8-cineole in the blood, 11.15 nl/g, approached that in the breathing air, 13.65 nl/ml. Inhalation and oral administration of various doses of rosemary oil produced dose-related increases in blood levels of 1,8-cineole. An increase in locomotor activity was observed in both cases. The disappearance of 1,8-cineole from the blood immediately after the termination of a 60-min inhalation period was biphasic: a rapid phase of elimination of about 10 min with a short blood half life (t/2 = 6 min) was followed by a slower rate of elimination (t/2 = 45 min). Since the blood levels of 1,8-cineole (if taken as an indicator for the blood levels of rosemary oil) associated with the stimulation of locomotor activity were similar regardless of whether the oil was administered by inhalation or orally, it is suggested that the stimulation of locomotor activity by rosemary oil is due at least in part to the direct pharmacological action of one or more of its constituents.
 
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Ikhlas Khan
  • University of Mississippi
Victor Kuete
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Olivier Potterat
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Thomas Efferth
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Matthias Hamburger
  • University of Basel