Antimicrobial activity and stability of tingenone derivatives.

Quinone-methide triterpenes of the tingenone series were evaluated for their antimicrobial activity. These compounds were effective against Bacillus cereus, B. subtilis, Sarcina lutea, Staphylococcus aureus, Microsporum gypseum and a Gram-negative bacterium, Klebsiella pneumoniae. Under acidic conditions, the quinone-methide part of these compounds rearranged into the divinyl-phenolic system, and the antimicrobial activity was thus lost.     

Cytotoxic activity of polyacetylenes and polyenes isolated from roots of Echinacea pallida

BACKGROUND AND PURPOSE: The n-hexane extracts of the roots of three medicinally used Echinacea species exhibited cytotoxic activity on human cancer cell lines, with Echinacea pallida found to be the most cytotoxic. Acetylenes are present in E. pallida lipophilic extracts but essentially absent in extracts from the other two species. In the present study, the cytotoxic effects of five compounds, two polyacetylenes (namely, 8-hydroxy-pentadeca-(9E)-ene-11,13-diyn-2-one (1) and pentadeca-(9E)-ene-11,13-diyne-2,8-dione (3)) and three polyenes (namely, 8-hydroxy-pentadeca-(9E,13Z)-dien-11-yn-2-one (2), pentadeca-(9E,13Z)-dien-11-yne-2,8-dione (4) and pentadeca-(8Z,13Z)-dien-11-yn-2-one (5)), isolated from the n-hexane extract of E. pallida roots by bioassay-guided fractionation, were investigated and the potential bioavailability of these compounds in the extract was studied. EXPERIMENTAL APPROACH: Cytotoxic effects were assessed on human pancreatic MIA PaCa-2 and colonic COLO320 cancer cell lines. Cell viability was evaluated by the WST-1 assay and apoptotic cell death by the cytosolic internucleosomal DNA enrichment and the caspase 3/7 activity tests. Caco-2 cell monolayers were used to assess the potential bioavailability of the acetylenes. KEY RESULTS: The five compounds exhibited concentration-dependent cytotoxicity in both cell types, with a greater potency in the colonic cancer cells. Apoptotic cell death was found to be involved in the cytotoxic effect of the most active, compound 5. Compounds 2 and 5 were found to cross the Caco-2 monolayer with apparent permeabilities above 10 x 10(-6) cm s(-1). CONCLUSIONS AND IMPLICATIONS: Compounds isolated from n-hexane extracts of E. pallida roots have a direct cytotoxicity on cancer cells and good potential for absorption in humans when taken orally.     

Antiproliferative effects of abietane diterpenoids isolated from Hyptis martiusii Benth (Labiatae)

Two abietane diterpenes were isolated from a hexane extract of Hyptis martiusii roots and identified as carnasol 11,14-dihidroxy-8,11,13-abietatrien-7-one. These compounds were tested for their antiproliferative effects on tumor cell lines using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide and on the sea urchin egg development. Both compounds displayed cytotoxic activity against tumor cell lines, but only carnasol was able to inhibit the sea urchin egg cleavages.     

New aminophenoxazinones from a marine Halomonas sp.: fermentation, structure elucidation, and biological activity

The addition of anthranilic acid to the culture medium of the marine derived Halomonas sp. strain GWS-BW-H8hM completely altered the secondary metabolite pattern relative to the standard conditions. The red-orange color of the culture filtrate extract was the result of the production of 2-aminophenoxazin-3-one (1), chandrananimycin C (5) and three new derivatives of 1 with a previously unknown substitution pattern: 2-amino-, 2-amino-8-benzoyl-, and 2-amino-8-(4-hydroxybenzoyl)-6-hydroxyphenoxazin-3-one (2-4). The compounds were determined to have antibacterial and cytotoxic activities; a mode of action other than DNA intercalation is discussed.     

Potentially Cytotoxic Triterpenoids from the Root Bark of Siphonodon celastrineus Griff.

A new oleanane-triterpene, 3beta-acetoxy-11alpha-benzoyloxy-13beta-hydroxyolean-12-one (1), was isolated along with a known quinone-methide triterpene, pristimerin (2), from the root bark of Siphonodon celastrineus Griff., a Thai medicinal plant of the family Celastraceae. Their structures were determined based on spectroscopic analysis.     

Synthesis, cytotoxic activity, and mechanism of action of furo[2,3-c]acridin-6-one and benzo[b]furo[3,2-h]acridin-6-one analogues of psorospermin and acronycine

Compounds possessing the epoxyfuran system present in the natural cytotoxic dihydrofuroxanthone psorospermin (4) fused onto the acridone or benzo[b]acridone chromophores present in the antitumor acronycine (1) and S23906-1 (3) were prepared. The basic furoacridone and benzofuroacridone cores bearing an isopropenyl substituent at a convenient position were synthesized by condensation of 1,3-dihydroxyacridone (7) or 1,3-dihydroxybenz[b]acridin-12(5H)-one (9) with (E)-1,4-dibromo-2-methylbut-2-ene. In both series, the (2R*,1'S*) epoxides, with the same relative configuration as psorospermin, were the most active compounds, exhibiting cytotoxic properties with IC50 values in the 10-100 nM range. As in the acronycine and psorospermin series, the new compounds act through alkylation of the DNA guanine units. However, a strong difference was noted in the DNA alkylation site between the benzopyranoacridone S23906-1, which alkylates DNA guanine units at position N-2 in the minor groove, and the new 13H-benzo[b]furo[3,2-h]acridin-6-one derived epoxide 21, which alkylates DNA guanine units at position N-7 in the major groove.     

Cytotoxic effects of three new metabolites from Red Sea marine sponge,Petrosia sp.

Marine sponges represent an affluent source of biogenetically unprecedented array of biologically active compounds. This study revealed the isolation of ten compounds from marine sponge of Petrosia sp. Their chemical structures were determined by using 1D and 2D NMR, UV, IR and MS measurements. A polyoxygenated steroid (3β,7β,9α-trihydroxycholest-5-en (1), a purine-derivative (3,7-dimethyl-2-(methylamino)-3H-purin-6(7H)-one (2) and a sphingolipid (N-((3S,E)-1,3-dihydroxytetracos-4-en-2-yl)stearamide (3) proved to be new compounds. Meanwhile, seven known compounds; (4–10) were also identified. The cytotoxicity of the total extract and the isolated compounds were subjected to cytotoxicity evaluation employing two cancer cell lines; HepG2 and MCF-7. All tested compounds exhibited cytotoxic effect on both cancer cell lines with IC₅₀ in range of 20-500 μM. The proposed mechanism of cytotoxic activities was examined through its molecular affinity to the DNA. Compound 5 showed the highest affinity to the DNA with IC₅₀ 30 μg/mL.     

Release of intermediate reactive hydrogen peroxide by macrophage cells activated by natural products

By determining the hydrogen peroxide (H2O2) released in cultures of peritoneal macrophage cells from Swiss mice, we evaluated the action of 27 vegetable compounds (pristimerin, tingenone, jatrophone, palustric acid, lupeol, cladrastin, ocoteine, boldine, tomatine, yohimbine, reserpine, escopoletin, esculine, plumericin, diosgenin, deoxyschizandrin, p-arbutin, mangiferin, and others) using a 2 mg/ml solution of each compound (100 microg/well). Macrophages are cells responsible for the development of the immunological response reaction, liberating more than one hundred compounds into the extracellular environment. Among these are the various cytokines and the intermediate compounds of nitrogen (NO) and oxygen (H2O2). This coordinated sequence of biochemical reactions is known as the "oxidative burst." When we compared the results with those obtained with zymosan (an important stimulator of H2O2) we observed that the compounds showing the highest activity were substances 2 (tingenone), 16 (reserpine) and 20. Other substances such as compounds 1, 4, 5, 6, 8, 12, 13, 14, 15, 17, 19, 23, 24, 26, and 27 also showed a certain activity, but with less intensity than the aforementioned ones. Compounds 3, 7, 9, 10, 11, 18, 21, 22 and 25 presented no activity. These results suggest that natural products (mainly tingenone and reserpine and others) with different chemical structures are strong immunological modulators. However, further tests are needed to determine the 'oxidative burst' in future studies.     

Physicochemical,Pharmacokinetic and Cytotoxicity of the Compounds Isolated from an Endophyte Fusarium oxysporum: In Vitro and In Silico Approaches

The present study was intended to characterize the secondary metabolites of the endophyte Fusarium oxysporum isolated from the plant Aglaonema hookerianum Schott. And to investigate the cytotoxic and other pharmacological properties of the isolated compounds as part of the drug discovery and development process. Different chromatographic techniques were adopted to isolate the bioactive compounds that were identified by spectroscopic techniques. The cytotoxic properties of the compounds were assessed in the Vero cell line via the trypan blue method. Moreover, physicochemical, pharmacokinetic, bioactivity and toxicity profiles of the compounds were also investigated through in silico approaches. After careful spectral analysis, the isolated compounds were identified as 3β,5α-dihydroxy-ergosta-7,22-dien-6-one (1), 3β,5α,9α-trihydroxy-ergosta-7,22-dien-6-one (2), p-hydroxybenzaldehyde (3), 3-(R)-7-butyl-6,8-dihydroxy-3-pent-11-enylisochroman-1-one (4) and beauvericin (5). An in vitro study in the Vero cell line revealed that the presence of the compounds reduced the number of cells, as well as the percentage of viable cells, in most cases. An in silico cytotoxic analysis revealed that compounds 1, 2 and 5 might be explored as cytotoxic agents. Moreover, compounds 3 and 4 were found to be highly mutagenic. The present study suggested that further thorough investigations are necessary to use these molecules as leads for the cytotoxic drug development process.     

真菌Penicillium sp. DT-F27次级代谢产物及其活性研究

摘要：目的 一株海洋来源真菌Penicillium sp. DT-F27次级代谢产物及其抗肿瘤活性的研究。方法 采用硅胶柱色谱、反相高效液相制备色谱等方法,对该真菌发酵产物的乙酸乙酯提取物进行分离纯化;采用波普解析方法对化合物的结构进行鉴定;采用MTT法测定化合物对人前列腺癌PC-3细胞的抗肿瘤作用。结果 从真菌Penicillium sp. DT-F27的发酵物中分离得到15个化合物,分别为麦角甾醇（1）,dehydrocyclopeptine（2）,3-O-methylviridicatin（3）,verrucofortine（4）,cyclopenin（5）,cyclo(dehydroala-L-Leu)（6）,cyclopenol（7）,4-hydroxy-2-methoxy acetanilide（8）,trans-(3RS,4RS)-3,4-dihydro-3,4,8-trihydroxynaphthalen-1(2H)-one（9）,cyclo(D-Pro-D-Val)（10）,brevianamide F（11）,cyclo(L-Pro-L-Val)（12）,anacine（13）,cyclo(L-Orn-L-Tyr-L-Orn-L-Ala)（14）,cyclo(L-Pro-L-Tyr)（15）。结论 从真菌Penicillium sp. DT-F27的次级代谢产物中分离15化合物,其中麦角甾醇（1）和3-O-methylviridicatin（3）具有较强的抗肿瘤活性,抑制率分别为45.6%和34.8%。     

Triterpene quinone-methides from Gymnosporia montana

Iguesterin, pristimerin, tingenone, beta-amyrin, beta-sitosterol and maytenonic acid have been isolated from the light petroleum extract of the stem bark and iguesterin, pristimerin, tingenone, beta-amyrin and beta-sitosterol from the root bark of Gymnosporia montana.     

Triterpene Quinone-Methides from Gymnosporia montana.

Iguesterin, pristimerin, tingenone, beta-amyrin, beta-sitosterol and maytenonic acid have been isolated from the light petroleum extract of the stem bark and iguesterin, pristimerin, tingenone, beta-amyrin and beta-sitosterol from the root bark of GYMNOSPORIA MONTANA.     

Structure-activity relationships and mechanism of action of antitumor benzo[b]pyrano[3,2-h]acridin-7-one acronycine analogues

The cytotoxic and antitumor activities of cis-1,2-diacyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one derivatives 3, 6-9 were strongly correlated with their ability to give covalent adducts with purified, as well as genomic, DNA. Such adducts involve reaction between the exocyclic N-2 amino group of guanines exposed in the minor groove of double helical DNA and the leaving ester group at the benzylic position 1 of the drug. A transesterification process of the ester group from position 2 to position 1 in aqueous medium accounted for the intense activity of the cis-1-hydroxy-2-acyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one derivatives 10-13. Compounds without acyloxy or hydroxy group at position 1, such as 15, 17, 18, and 22, were inert with respect to DNA and almost devoid of significant cytotoxic activity. Condensation of 5-amino-2,2-dimethyl-2H-chromene (26) with 3-bromo-2-naphthoic acid (27), followed by cyclization, gave access to 6-demethoxy analogues. Diacetate 32 and cyclic carbonate 33, both belonging to the latter series, were less reactive toward DNA and less cytotoxic than their 6-methoxy counterparts 3 and 34. DNA alkylation appears thus to play an important role in the antitumor properties of benzo[b]pyrano[3,2-h]acridin-7-one derivatives.     

Chemical modification of alisol B 23-acetate and their cytotoxic activity

The twelve-protostane analogues were synthesized from alisol B 23-acetate and assessed for their in vitro antitumor activity against six different human and murine tumor cell lines. Of the compounds synthesized, 23S-acetoxy-24R(25)-epoxy-11beta,23S-dihydroxyprotost-13(17)-en-3-hydroxyimine (12) exhibited significant cytotoxic activities against A549, SK-OV3, B16-F10, and HT1080 tumor cells with ED50 values of 10.0, 8.7, 5.2, and 3.1 microg/ml, respectively. Furthermore, 23S-acetoxy-13(17),24R(25)-diepoxy-11beta-hydroxyprotost-3-one (5), 13(17),24R(25)-diepoxy-11beta,23S-dihydroxyprotostan-3-one (6), 24R,25-epoxy-11beta,23S-dihydroxyprotost-13(17)-en-3-one (7), and 11beta,23S,24R,25-tetrahydroxyprotost-13(17)-en-3-one (9) showed moderate cytotoxic activities against B16-F10 and HT1080 tumor cells. These results mean that a hydroxyimino group at C-3 position in the protostane-type terpene enhances cytotoxic activity.     

Potentially bioactive two new natural sesquiterpenoids from the rhizomes ofZingiber zerumbet

Repeated chromatography of the n-hexane-soluble fraction of the MeOH extract of the rhizomes of Zingiber zerumbet led to the isolation of two isomers of 6-methoxy-2E,9E-humuladien-8-one (1 and 2) and stigmast-4-en-3-one. The structures of 1 and 2 were determined by spectroscopic methods including 1 D and 2D-NMR elucidated by analysis of spectroscopic data as well as by comparison with published values. This is the first report on the isolation of compounds 1 and 2 from the nature. Stigmast-4-en-3-one was first isolated from this plant.     

Cytotoxic compounds of Schizolaena hystrix from the Madagascar rainforest

Bioassay-guided fractionation of a crude ethanol extract from a Madagascar collection of Schizolaena hystrix afforded the two new long-chain compounds, 3 S-acetoxyeicosanoic acid ethyl ester ( 1) and 3 S-acetoxydoeicosanoic acid ( 2), and the known long-chain compound 3 S-acetoxyeicosanoic acid ( 3). In addition, the long-chain alcohol 1-hydroxydodecan-2-one ( 7), as well as the new flavonoid schizolaenone C ( 4) and the two known flavonoids diplacol ( 5) and 3'-prenylnaringenin ( 6) were isolated from a methanol extract of the same plant. Isolation and structure elucidation of the novel compounds and the cytotoxicities of all the isolates are reported.     

Antimicrobial constituents from fruits ofAilanthus altissima SWINGLE

A new naturally occurring sterol, compound 5, and six known stigmasterols were isolated from fruits of Ailanthus altissima Swingle by repeated column chromatography and RP-HPLC. Their structures were identified as, 5alpha-stigmastane-3,6-dione (1), 3beta-hydroxystigmast-5-en-7-one (2), stigmast-5-ene-3beta, 7alpha-diol (3), 6alpha-hydroxystigmast-4-en-3-one (4), 5alpha-stigmastane-3beta, 6beta-diol (5), stigmast-4-ene-3beta, 6alpha-diol (6), stigmast-5-ene-3beta, 7alpha, 20xi-triol (7) by spectral analysis and comparison with the published data. These compounds have not been reported from genus Ailanthus, whereas compound 7 was identified by NMR for the first time. In addition, the 95% ethanol extract and compounds from the fruits of Ailanthus altissima SWINGLE were assayed for in vitro antimicrobial activity. The extract was potent active against the assayed bacteria while compounds 3 and 7 exhibited moderate activity.     

Chemical synthesis,molecular modelling,and evaluation of anticancer activity of some pyrazol-3-one Schiff base derivatives

A series of twelve pyrazol-3-one Schiff`s base derivatives (5–17) were designed and synthesized by microwave-assisted chemical synthesis. Their purity was confirmed by melting point and HPLC and their chemical structures were determined by FT-IR, UV, <sup>1</sup>H, and <sup>13</sup>C-NMR spectroscopic techniques. In silico docking of the synthesized compounds inside the active site of thymidine phosphorylase was performed using two molecular modeling programs. The compounds were tested in vitro on calf thymus DNA to study the interaction with DNA using a spectrophotometer. Some of the pyrazol-3-one Schiff`s base derivatives showed close match interaction with DNA. The tested compounds were also studied by application to angiogenic enzyme thymidine phosphorylase (TP, E.C. 2.4.2.4), carcinoma cell lines including both human breast (MCF-7) and human lung cell lines (A549). The lead compound 2 in the series caused inhibition of thymidine phosphorylase in the micro molar range (IC₅₀ of 28 ± 2 µM) and was able to retard growing of breast carcinoma cells. Our results indicate that pyrazol-3-one Schiff base derivatives are promising lead compounds for the development of more active antitumor agents and exhibit their highest cytotoxic effect on breast carcinoma cell line.     

Studies on di- and triterpenoids from Salvia staminea with cytotoxic activity

A new ursane-type triterpenoid, 3 beta,11 alpha,21 alpha-trihydroxyurs-12-ene, named salvistamineol (1), has been isolated from the methanol extract of Salvia staminea. In addition to 1, the methanol extract yielded four known compounds and the acetone extract yielded twelve known compounds consisting of two sesquiterpenes, six diterpenoids, a triterpenoid, two steroids and one flavone. DNA damaging properties of the extracts and some isolated diterpenes were investigated against three yeasts and only taxodione gave a positive response and also showed the highest cytotoxic activity against a panel of cell lines among the investigated compounds in this study.     

Bioactive coumarin derivatives from the fern Cyclosorus interruptus

Three new coumarin derivatives, compounds 1-3, three new furanocoumarins, compounds 4-6, and a novel dioxocane derivative, compound 7, were isolated from the fern Cyclosorus interruptus (Willd.) H. It?. Based on spectrometric and spectroscopic analysis (FAB or El mass spectrometry as well as 1D and 2D NMR experiments) their structures were characterised as 5,7-dihydroxy-6-methyl-4-phenyl-8-(3-phenylpropionyl)-1-benzopyran-2-one (1), 5,7-dihydroxy-6-methyl-4-phenyl-8-(3-phenyl-trans-acryloyl)-1- benzopyran-2-one (2), 5,7-dihydroxy-8-(2-hydroxy-3-phenylpropionyl)-6-methyl-4-phenyl-1- benzopyran-2-one (3), 8-benzyl-5,8-dihydroxy-6-methyl-4-phenylfuro[2,3-h]-1-benzopyran-2,9- dione (4), 8-benzyl-5,8 beta,9 beta-trihydroxy-6-methyl-4-phenyl-8,9-dihydro- furo[2,3-h]-1-benzopyran-2-one (5), 8-benzyl-5,8 beta,9 alpha-trihydroxy-6-methyl-4-phenyl-8,9-dihydro- furo[2,3-h]-1-benzopyran-2-one (6) and 5,11-dihydroxy-6-methyl-4-phenyl-11-(1-phenylmethyl)-7,10-dioxocane [5,6-h]-1-benzopyran-2,12-dione (7). For these compounds we propose the trivial names interruptins A-F. Compounds 1, 5/6 and 7 showed antibacterial activity while compounds 1 and 2 were cytotoxic to a KB cell line.