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PubMed2004

Toxicological profiling of sediments using in vitro bioassays, with emphasis on endocrine disruption.

In vitro bioassays are valuable tools for screening environmental samples for the presence of bioactive (e.g., endocrine-disrupting) compounds. They can be used to direct chemical analysis of active compounds in toxicity identification and evaluation (TIE) approaches. In the present study, five in vitro bioassays were used to profile toxic potencies in sediments, with emphasis on endocrine disruption. Nonpolar total and acid-treated stable extracts of sediments from 15 locations in the Rhine Meuse estuary area in The Netherlands were assessed. Dioxin-like and estrogenic activities (using dioxin-responsive chemical-activated luciferase gene expression [DR-CALUX] and estrogen-responsive chemical-activated luciferase gene expression [ER-CALUX] assays) as well as genotoxicity (UMU test) and nonspecific toxic potency (Vibrio fischeri assay) were observed in sediment extracts. For the first time, to our knowledge, in vitro displacement of thyroid hormone thyroxine (T4) from the thyroid hormone transport protein thransthyretin by sediment extracts was observed, indicating the presence of compounds potentially able to disrupt T4 plasma transport processes. Antiestrogenic activity was also observed in sediment. The present study showed the occurrence of endocrine-disrupting potencies in sediments from the Dutch delta and the suitability of the ER- and DR-CALUX bioassays to direct endocrine-disruption TIE studies.

Biological Assay↗
PubMed1990

The effect of somatostatin on the production of human interferons by mononuclear cells.

Somatostatin (SMS) is a tetradecapeptide which can inhibit the secretion of a number of peptides produced by the endocrine or nervous systems. SMS 201-995 (octreotide) is a somatostatin analogue with very potent somatostatin activities. We have been investigating the effects of both SMS and octreotide on the production of human interferon (IFN). We obtained human peripheral blood mononuclear cells from normal donors and induced them to produce IFN in the presence or absence of a number of peptides possessing somatostatin activities. SMS and octreotide were shown to inhibit the secretion of INF-gamma but not IFN-alpha. Concentrations of 10(-6) M were shown to decrease yields when Concanavalin A or phytohemagglutin were used as the inducer. Higher concentrations had a progressively greater effect. No effects were observed on IFN-gamma production if interleukin 2, ionomycin, or various natural antigens were used to induce the cells. The 28-amino acid form of somatostatin had some effects on gamma IFN yields but the first 14-amino acid fragment of this peptide moiety did not. No effect of any of these compounds was observed on IFN bioactivity. These studies indicate SMS may have some regulatory action on the secretion of immunomodulators in vitro but the concentrations required are well above those encountered under physiologic circumstances, suggesting SMS may not play an important regulatory role governing such secretion in vivo.

Concanavalin A↗
PubMed1985

Spectinomycin modification. II. Spectinomycin C-3'-modification via diazoketone intermediates.

The C-3'-carbonyl group of N-protected spectinomycin is efficiently converted into a diazo group via base treatment of the corresponding tosylhydrazone. The diazo group imparts a new synthetically useful reactivity pattern on the sugar ring of the molecule. The synthesis of C-3'-deoxo-, monohalo- and dihalospectinomycins via the intermediacy of these diazo compounds is described. The reduced bioactivity of these analogs as compared to the parent and the C-3'-dihydro and aminospectinomycins established the need for hydrogen bonding groups in this region of the molecule for good activity, further refining the structure activity relationships in the spectinomycin series.

Chemical Phenomena↗
PubMed2000

Genetically modified Chinese hamster ovary cells for investigating sulfotransferase-mediated cytotoxicity and mutation by 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine.

To test the hypothesis that the sulfotransferase gene plays a role in the phase II bioactivation of PhIP, a heterocyclic amine found in cooked meats, we transfected the UV5P3 cell line with cDNA plasmids of human aryl sulfotransferases (HAST1 and HAST3). UV5P3 is a nucleotide excision repair-deficient and P4501A2-expressing CHO cell line that we have previously developed. Functionally transformed clones were identified by the differential cytotoxicity (DC) assay that used PhIP as the cytotoxic agent. Two clones designated 5P3H1 and 5P3H3, expressing HAST1 and HAST3, respectively, were chosen for further characterization. Correct fragment sizes of the sulfotransferase cDNAs were identified in both cell lines by polymerase chain reaction. Immunoblot analysis confirmed the expression of the sulfotransferase proteins. The addition of the sulfotransferase inhibitor DCNP decreased the cytotoxic effects of PhIP in a dose-dependent manner. The increase in cell growth was 6. 5-fold for 5P3H1 and 2.4-fold for 5P3H3, relative to values obtained without DCNP. Based on D(50) values, the dose that reduced the survival to 50% relative to untreated controls, the cytotoxic effect of PhIP was increased threefold for 5P3H1 and 1.87-fold for 5P3H3 cell lines over the parental UV5P3 line. There was also a small increase in the mutation response at the aprt locus. These newly established 5P3H1 and 5P3H3 sulfotransferase-expressing cells provide valuable mechanistic information of the bioactivation of PhIP and related compounds. Environ. Mol. Mutagen. 35:57-65, 2000. Published 2000 Wiley-Liss, Inc.

Animals↗
PubMed2000

[Determination of effective components in propolis].

Propolis is a resinous hive product collected by bees. Propolis is a complex mixture of phenols, acids, alcohol and flavonoids. The aim of the present work is to study the effective components present in propolis and to confirm its biological activities. Four extracts from propolis were obtained by using different organic solutions. Further separation and identification were carried out by capillary gas chromatography and mass spectrometry(CGC/MS). The CGC/MS analysis on propolis extracted by different solvents resulted in more than 80 compounds being separated. Another 38 bioactive materials, including 6 alcohol, 5 phenols, 6 acids, 6 flavonoids and 13 others, have been identified.

Animals↗
PubMed2003

Discovery and evaluation of inhibitors of human sphingosine kinase.

Sphingolipid-metabolizing enzymes control the dynamic balance of the cellular levels of bioactive lipids, including the proapoptotic compound ceramide and the proliferative compound sphingosine 1-phosphate. Accumulating evidence indicates that sphingosine kinase (SK) plays a pivotal role in regulating tumor growth and that SK can act as an oncogene. Despite the importance of SK for cell proliferation, pharmacological inhibition of SK is an untested means of treating cancer because of the current lack of nonlipid inhibitors of this enzyme. To further assess the involvement of SK in human tumors, levels of RNA for SK in paired samples of cDNA prepared from tumors and normal adjacent tissue were analyzed. Expression of SK RNA was significantly elevated in a variety of solid tumors, compared with normal tissue from the same patient. To identify and evaluate inhibitors of SK, a medium throughput assay for recombinant human SK fused to glutathione S-transferase was developed, validated, and used to screen a library of synthetic compounds. A number of novel inhibitors of human SK were identified, and several representative compounds were characterized in detail. These compounds demonstrated activity at sub- to micromolar concentrations, making them more potent than any other reported SK inhibitor, and were selective toward SK compared with a panel of human lipid and protein kinases. Kinetic studies revealed that the compounds were not competitive inhibitors of the ATP-binding site of SK. The SK inhibitors were antiproliferative toward a panel of tumor cell lines, including lines with the multidrug resistance phenotype because of overexpression of either P-glycoprotein or multidrug resistance phenotype 1, and were shown to inhibit endogenous human SK activity in intact cells. Furthermore, each inhibitor induced apoptosis concomitant with tumor cell cytotoxicity. Methods for the synthesis of a series of aurone inhibitors of SK were established, and a prototypical dihydroxyaurone was found to have moderate antitumor activity in vivo in the absence of overt toxicity to the mice. These compounds are the first examples of nonlipid inhibitors of SK with in vivo antitumor activity and so provide leads for additional development of inhibitors of this important molecular target.

Animals↗
PubMed2003

Isolation of an anti-tumour terpenoid from stem bark of Spondianthus preussii var. preussii Engl.

We report a biologically monitored phytochemical separation of stem bark of Spondianthus preussii var. preussii against a panel of human cancer cell lines in vitro and the P-388 murine lymphocytic leukemia cells in culture. An ethylacetate extract of the stem bark exhibited selective cytotoxicity against human melanoma (ED50 = 10.0 ug/ml). Further activity-guided fractionation of the ethylacetate extract by flash chromatography and subsequent purification on preparative thin layer chromatography led to the identification of a lupane-type triterpene, 3beta-hydroxy-20(29)--lupenoic acid, by spectroscopic methods. This is the first report of the occurrence of this compound in S. preussii var. preussii. It is also the first time this triterpene is being shown to exhibit in vitro anti-tumor activity against human melanoma (ED50 = 2.4 ug/ml). This compound could be a promising bioactive natural product since it has been previously reported to exhibit a range of biological activities including in vivo and in vitro antiplasmodial activity and it is not toxic.

Animals↗
PubMed2006

[Structural modification of cyclovirobuxine D and their inhibition activity on lipid peroxidation].

AIM: To search for compounds through structural modification of cyclovirobuxine D, using 20 or 21-aminosteroids as lead compound for the treatment of cerebrovascular diseases with better lipid peroxidation inhibitory activity. METHODS: According to rational drug design principle, a series of cyclovirobuxine D analogues were prepared, and their bioactivities were tested. RESULTS: Four new compounds were obtained and confirmed by spectra. CONCLUSION: Lipid peroxidation inhibitory effects of cyclovirobuxine D analogues were tested by using TBA method. Some compounds showed better activity than that of cyclovirobuxine D.

Animals↗
PubMed1993

Biotransformation to nitric oxide of organic nitrates in comparison to other nitrovasodilators.

Nitrovasodilators are prodrugs which, although chemically heterogenous, exert their pharmacodynamic action via a common pathway, i.e. the release of nitric oxide (NO). The NO, which results from metabolism of nitrovasodilators in vascular and non-vascular cells, stimulates the cytosolic enzyme guanylyl cyclase leading to an increase in the concentration of intracellular cyclic guanosine monophosphate (cGMP). In general, the rate of NO generation from the individual compounds correlates well with the extent of cGMP increase and their potency to relax vascular tissue. The amounts of NO generated are sufficient to inhibit platelet aggregation and to induce disaggregation. Nitrovasodilators thus mimic the action of endothelium-derived relaxing factor (EDRF). After more than a century of empiric use, the application of nitrovasodilators today may be regarded as causal therapy, since these drugs act by substituting an endogenous factor, the production or release of which is impaired under pathophysiological circumstances associated with endothelial dysfunction. Marked differences exist between individual compound classes with regard to bioactivation mechanisms, cofactor requirements, and the extent and nature of the concomittant formation of metabolites other than NO. This review describes the discovery of the mode of action of nitrovasodilators and our current understanding of the pathways involved in their bioactivation and biodegradation with special emphasis on the enzymatic and non-enzymatic metabolism of organic nitrates. In addition, the in-vivo metabolism of NO is reviewed briefly.

Biotransformation↗
PubMed1999

Inhibitory effect of luteolin 4'-O-glucoside from Kummerowia striata and other flavonoids on interleukin-5 bioactivity.

Interleukin (IL)-5 is a chemotactic factor of eosinophils, and promotes the growth and survival of eosinophils, which plays an important role in the eosinophilia-associated allergic inflammation. In this study, luteolin 4'-O-glucopyranoside was identified as the IL-5 inhibitor from Kummerowia striata Thunb. (Leguminosae) by activity-guided fractionation followed by structural analysis compared with reported spectral data. The flavone compound exhibited dose-dependent inhibitory effect on IL-5 bioactivity with 95% inhibition at 30 microM, 79% at 15 microM, 60% at 7.5 microM, 54% at 3.8 microM and 29% at 1.9 microM, where 50% of inhibition (IC50) value was shown at the concentration of 3.7 microM. Furthermore, the inhibitory effect on IL-5 bioactivity by other flavonoid compounds available was estimated. In view of the IC50 values, the inhibitory potency on IL-5 bioactivity was in order of luteolin 4'-O-glucopyranoside > cosmosiin (14.2 microM) approximately equal to apigenin (16.4 microM) approximately equal to luteolin (18.7 microM) > quercimeritrin (27.3 microM) approximately equal to kaempferol (30.0 microM).

Animals↗
PubMedDate not supplied

Improved electron-conformational method of pharmacophore identification and bioactivity prediction. Application to angiotensin converting enzyme inhibitors.

The electron-conformational (EC) method of pharmacophore (Pha) identification and bioactivity prediction, suggested earlier, is given here two major improvements. First, an atomic index of orbital and charge controlled interaction is introduced to better represent the ligand (substrate) in its interaction with the bioreceptor. Second, the multiconformational problem is considered in view of ligand-receptor binding states, resulting in essential simplification of the expression of bioactivity. The details of the improved EC method are demonstrated in application to the problem of angiotensin converting enzyme (ACE) inhibitors. The Pha of the latter is identified by separation of the heavily populated conformations of the chosen 51 compounds (the training set), calculation of the electronic structure, construction of their EC matrixes of congruity, and processing of the latter in comparison with the activities to reveal a common submatrix of all the active only compounds that describes the Pha. The latter contains three oxygen atoms plus a fourth atom X = S, N, O at certain interatomic distances and with restricted electronic parameters (within assumed tolerances), the position of the atom X being more changeable from one active compound to another. For quantitative prediction of the bioactivity, an expression is deduced which takes into account the duly parametrized influence of auxiliary groups (AG) which, being positioned outside the Pha, either diminish the activity (antipharmacophore shielding) or enhance it. It is shown that in case of many conformations of the same compound only one of them, that of the lowest energy which has the Pha, should be parametrized. The 15 parameters chosen to represent the AG in case of ACE inhibitors are weighted by variational (adjustable) coefficients which are determined from a regression treatment of the calculated versus known activities in the training set. Then the formulas with known coefficients are used to validate the method by calculating the bioactivity of other compounds not used in the training set. The prediction of the activity proved to be more than 90% (within experimental error and available compounds) qualitatively (yes, no) and about 60%-70% quantitatively.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

Acrolein in cigarette smoke inhibits T-cell responses.

BACKGROUND: Cigarette smoking inhibits T-cell responses in the lungs, but the immunosuppressive compounds have not been fully identified. Cigarette smoke extracts inhibit IL-2, IFN-gamma, and TNF-alpha production in stimulated lymphocytes obtained from peripheral blood, even when the extracts were diluted 100-fold to 1000-fold. OBJECTIVE: The objective of these studies was to identify the immunosuppressive compounds found in cigarette smoke. METHODS: Gas chromatography/mass spectroscopy and HPLC were used to identify and quantitate volatile compounds found in cigarette smoke extracts. Bioactivity was measured by viability and production of cytokine mRNA and protein levels in treated human lymphocytes. RESULTS: The vapor phase of the cigarette smoke extract inhibited cytokine production, indicating that the immunosuppressive compounds were volatile. Among the volatile compounds identified in cigarette smoke extracts, only the alpha,beta-unsaturated aldehydes, acrolein (inhibitory concentration of 50% [IC50] = 3 micromol/L) and crotonaldehyde (IC50 = 6 micromol/L), exhibited significant inhibition of cytokine production. Although the levels of aldehydes varied 10-fold between high-tar (Camel) and ultralow-tar (Carlton) extracts, even ultralow-tar cigarettes produced sufficient levels of acrolein (34 micromol/L) to suppress cytokine production by >95%. We determined that the cigarette smoke extract inhibited transcription of cytokine genes. The inhibitory effects of acrolein could be blocked with the thiol compound N-acetylcysteine. CONCLUSION: The vapor phase from cigarette smoke extracts potently suppresses cytokine production. The compound responsible for this inhibition appears to be acrolein.

Acetylcysteine↗
PubMed2006

Heptamethine cyanine dyes with a robust C-C bond at the central position of the chromophore.

Novel, highly fluorescent, monofunctional, water-soluble heptamethine cyanine dyes containing a robust C-C bond at the central position of the near-infrared fluorophore system were prepared by the Suzuki-Miyaura method. The reaction proceeded efficiently to replace the meso-chlorine atom with a carboxy-functionalized aryl moiety and afforded the desired compounds in high yields. This methodology is particularly attractive due to its versatility and the utilization of environmentally friendly water as solvent. The new compounds possess excellent spectral properties and readily label bioactive molecules on solid support. The results demonstrate the potential of using the new compounds as fluorescent antennae for molecular imaging, spectroscopy, microscopy, and chemical or biological molecular recognition studies.

Carbocyanines↗
PubMed1994

Isolation of bioactive and other oxoaporphine alkaloids from two annonaceous plants, Xylopia aethiopica and Miliusa cf. banacea.

The oxoaporphine alkaloids oxophoebine [1] and liriodenine [2] have been isolated from Xylopia aethiopica (Annonaceae). Both showed selective toxicity against DNA repair and recombination deficient mutants of the yeast Saccharomyces cerevisae. Three related but inactive compounds, oxoglaucine [3], O-methylmoschatoline [4], and lysicamine [5], were also isolated from this plant. Selective toxicity was also observed for 10-methoxyliriodenine (lauterine) [6] and 10-hydroxyliriodenine [7], two oxoaporphine alkaloids isolated from Miliusa cf. banacea (Annonaceae). The structure of 10-hydroxyliriodenine [7], a novel oxoaporphine, was determined by spectroscopic methods and chemical conversion to compound 6. The role of the bioactive oxoaporphine alkaloids as DNA topoisomerase inhibitors is discussed.

Antineoplastic Agents, Phytogenic↗
PubMed1990

Synthesis and biological activity of novel vitamin D analogues: 24,24-difluoro-25-hydroxy-26,27-dimethylvitamin D3 and 24,24-difluoro-1 alpha,25-dihydroxy-26,27-dimethylvitamin D3.

We synthesized 24,24-difluoro-25-hydroxy-26,27-dimethylvitamin D3 (16), and 24,24-difluoro-1 alpha, 25-dihydroxy-26,27-dimethylvitamin D3 (21), from 3 beta-hydroxy-22,23-dinorcholenic acid 3-acetate. Compound 16 was found to be a highly potent vitamin D analogue with bioactivity similar to that of 25-hydroxyvitamin D3 in vivo. Compound 16 was bound by vitamin D binding protein with an affinity slightly less than that of 25-hydroxyvitamin D3. It was bound to the intestinal cytosol receptor for 1,25-dihydroxyvitamin D3 with approximately the same affinity as that of 25-hydroxyvitamin D3. In the organ-culture duodenum, 16 induced the synthesis of calcium binding protein with a potency approximately 1/20 that of 1,25-dihydroxyvitamin D3. Compound 21 was also noted to be a highly potent vitamin D analogue with bioactivity in vivo similar to that of 1,25-dihydroxyvitamin D3. It was bound to vitamin D binding protein with an affinity considerably less than that of 1,25-dihydroxyvitamin D3. It was bound to the intestinal cytosol receptor for 1,25-dihydroxyvitamin D3 with an affinity slightly less than that of the native hormone. In the organ-culture duodenum, 21 was noted to be about 3 times more active than 1,25-dihydroxyvitamin D3 in the induction of calcium binding protein. The introduction of fluorines at C-24 and extension of the sterol side chain at C-26 and C-27 by methylene groups results in vitamin D analogues that have biological activity in vivo similar to those of the respective nonfluorinated natural sterols.

Animals↗
PubMedDate not supplied

[Cytotoxic compounds from the marine actinobacterium].

We isolated a bioactive streptomycete from marine sediment samples collected at Bay of Bengal, India, during our systematic study of marine actinobacteria. The taxonomic studies indicated that the isolate is related to Strepomyces corchorusii. However, it differed in certain aspects, and, hence, was designated as S. corchorusii AUBN(1)/7. A solvent extraction followed by a chromatographic purification helped obtain from the isolate two cytotoxic compounds, which were identified as resistomycin, a quinone-related antibiotic, and tetracenomycin D, an anthraquinone antibiotic, on the basis of spectral data of pure compounds. They demonstrated in vitro a potent cytotoxic activity against cell lines HMO2 (gastric adenocarcinoma) and HepG2 (hepatic carcinoma) and also exhibited weak antibacterial activities against Gram-positive and Gram-negative bacteria. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2006, vol. 32, no. 3; see also http://www.maik.ru.

Antibiotics, Antineoplastic↗
PubMedDate not supplied

A cytotoxic and antifungal 1,4-naphthoquinone and related compounds from a New Zealand brown algae, Landsburgia quercifolia.

The bioactivity-directed isolation of deoxylapachol [I] from a New Zealand brown alga, Landsburgia quercifolia, is described. Compound I was active against P-388 leukemia cells (IC50 0.6 microgm/ml) and was also antifungal. 1,4-Dimethoxy-2-(3-methyl-2-butenyl)-naphthalene [3] was the major low polarity component of extracts of this seaweed, which also contained 2,3-dihydro-2,2-bis(3-methyl-2-butenyl)-1,4-naphthalenedione [6] and 2-(3-methyl-2-butenyl)-2,3-epoxy- 1,4-naphthalenedione 4,4-dimethoxy ketal [7]. Compound 7 was converted to the 2,3-epoxide of I, which had biological activities similar to those of I.

Animals↗