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PubMed2006

Bioactive constituents of brazilian red propolis.

In a new propolis type, red Brazilian propolis, 14 compounds were identified (six of them new for propolis), among them simple phenolics, triterepenoids, isoflavonoids, prenylated benzophenones and a naphthoquinone epoxide (isolated for the first time from a natural source). Three of the major components demonstrated significant antimicrobial activity, and two (obtained as inseparable mixture) possessed radical scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH).

Journal Article↗
PubMed2002

Oestrogenic activity of the hop phyto-oestrogen, 8-prenylnaringenin.

The female flowers of the hop plant (hop cones) are used as a preservative and as a flavouring agent in beer. A novel phyto-oestrogen, 8-prenylnaringenin, was recently identified in hops and this study was undertaken to characterize the oestrogenic activity of this compound using a combination of in vitro and in vivo assays. Natural and semi-synthetic 8-prenylnaringenin showed similar bioactivities both in a yeast screen transfected with the human oestrogen receptor and in oestrogen-responsive human Ishikawa Var-I cells. 8-Prenylnaringenin showed comparable binding activity to both oestrogen receptor isoforms (ER alpha and ER beta). 8-Prenylnaringenin extracted from hops contains similar amounts of both (R)- and (S)- enantiomers, indicating that the compound is normally formed non-enzymatically. Both enantiomers showed similar bioactivity in vitro and similar binding characteristics to ER alpha and ER beta. The oestrogenic activity of 8-prenyl-naringenin in vitro was greater than that of established phyto-oestrogens such as coumestrol, genistein and daidzein. The high oestrogenic activity was confirmed in an acute in vivo test using uterine vascular permeability as an end point. When the compound was given to ovariectomized mice in their drinking water, oestrogenic stimulation of the vaginal epithelium required concentrations of 100 mug ml(-1) (about 500-fold greater than can be found in any beer).

Animals↗
PubMed1996

Four new bioactive manzamine-type alkaloids from the Philippine marine sponge Xestospongia ashmorica.

Analysis of the Philippine marine sponge Xestospongia ashmorica afforded four new manzamine congeners 1-4 and four known compounds 5 and 7-9. Compound 1 is the 6-deoxy derivative of manzamine X, while 2-4 are the N-oxides of manzamine J (5), 3,4-dihydromanzamine A (6), and manzamine A (7), respectively. The structures of the new compounds were unambiguously established on the basis of NMR spectroscopic (1H, 13C, COSY, 1H-detected direct, and long-range 13C-1H correlations) and mass spectrometric (EI, FAB-MS, and electrospray ionization) data. Alkaloid N-oxide structures were confirmed by conversion to the corresponding tertiary bases by reduction with Zn/HCl. This is the first report of the occurrence of bioactive manzamine N-oxides in marine sponges. Compound 7 exhibited insecticidal activity toward neonate larvae of the polyphagous pest insect Spodoptera littoralis (with an ED50 of 35 ppm) when incorporated in artificial diet and offered to larvae in a chronic feeding bioassay. Compound 7 was also active against the Gram-positive bacteria Bacillus subtilis and Staphylococcus aureus. Cytotoxicity was studied in vitro using L1578y mouse lymphoma cells. From the alkaloids studied, the N-oxides 3 and 4 were the most active (ED50 = 1.6 micrograms/mL) followed by compound 7 (ED50 = 1.8 micrograms/mL).

Alkaloids↗
PubMed2000

Isolation and characterization of bioactive metabolites from marine-derived filamentous fungi collected from tropical and sub-tropical coral reefs.

Two new compounds, paecilospirone (1) and phomopsidin (2), and seven known compounds, chaetoglobosin A (3), griseofulvin (4), fusarielin A (5), fusapyrone (6), deoxyfusapyrone (7), and verrucarins J (8) and L acetate (9), have been isolated and characterized from marine-derived fungi collected in tropical and sub-tropical coral reef environments. The utility of marine-derived fungi as a source of bioactive secondary metabolites is discussed.

Animals↗
PubMed2006

Developmental therapeutics: review of biologically based CAM therapies for potential application in children with cancer: part I.

This article is a review of the status of biologically based complementary and alternative medicine (CAM) therapies that have potential anticancer activity with a focus on those agents that may be active in childhood cancer. The review presented in 2 parts includes the descriptions of the mechanisms that underlie their effects, the manner by which these agents are identified and evaluated and discussion of some of the limitations of current research. The first part introduces the topic of biologically based CAM therapies. The discussion includes a description the discovery biologically based products for cancer, the classification of these compounds and their use from the perspectives of the Ayurvedic and traditional Chinese medicine systems. Issues associated with evidence-based research of compounds used in these practices are addressed. The second part focuses on preclinical and clinical studies of specific herbs or natural products and their bioactive constituents that demonstrate potential in cancer therapeutics. Turmeric, mistletoe, green tea, ginseng, mushrooms, and micronutrients are representative of compounds that exert their effects through mechanisms attributed to specific chemical classes. The section concludes with a discussion of status of clinical trials of biologically based CAM therapeutics for cancer and the future direction of research.

Child↗
PubMed1993

Inhibition patterns of brain acetylcholinesterase and hepatic and plasma aliesterases following exposures to three phosphorothionate insecticides and their oxons in rats.

Rats were administered high sublethal intraperitoneal dosages of the phosphorothionate insecticides parathion, methyl parathion, and chlorpyrifos, and their oxons. Acetylcholinesterase activities in cerebral cortex and medulla oblongata and aliesterase activities in liver and plasma were monitored at 2 hr and 1, 2, and 4 days after exposure. The maximal inhibition of brain acetylcholinesterase activity was not immediate with parathion and chlorpyrifos, reflecting the time required for bioactivation of the phosphorothionates as well as the effectiveness of the aliesterases to inactivate much of the hepatically generated oxons. In contrast, brain acetylcholinesterase activities were more quickly inhibited following administration of paraoxon and chlorpyrifos-oxon, which do not require bioactivation. Brain acetylcholinesterase was also rapidly inhibited following administration of methyl parathion and methyl paraoxon, reflecting the low sensitivity of the aliesterases to methyl paraoxon. Aliesterases were inhibited to a greater extent than acetylcholinesterase at each sampling time with parathion and chlorpyrifos and their oxons, whereas the reverse was true with methyl parathion and methyl paraoxon. All of the above patterns correlate with the in vitro sensitivities of acetylcholinesterase and aliesterases to the oxons. The very prolonged inhibition of esterase activities following chlorpyrifos treatment probably results from its substantially greater lipophilicity compared to the other compounds, which would allow it to be stored and released for gradual bioactivation. The data reported indicate that the disposition and effects of different phosphorothionate insecticides will be influenced by the sensitivities of target and nontarget esterases for their oxons and by their lipophilicity, and that predictions of in vivo responses can be made from in vitro data.

Acetylcholinesterase↗
PubMed2003

Established theory of radiation-induced decay is not generalizable to Bolton-Hunter labeled peptides.

Peptide hormones radiolabeled with 125I are widely used for the pharmacological characterization of cognate receptors. As a prerequisite for calculating ligand affinities from competition binding assays, and for estimating receptor densities from such studies, it is necessary to know the concentration of bioactive radioligand that is used in respective experiments. It has been demonstrated previously that radioiodinated peptides undergo decay catastrophe, i.e. disintegration of the radioactive label leads to the concomitant destruction of the carrier peptide. Here, we demonstrate that decay catastrophe does not apply to two peptide hormones that are iodinated by Bolton-Hunter conjugation: cholecystokinin octapeptide and glucagon-like peptide 2. The function of aged samples of these radioligands at corresponding recombinantly expressed receptors was assessed by measuring ligand-induced inositol phosphate production or generation of cyclic AMP, respectively. Both of the tested compounds, although predicted by decay catastrophe to contain little or subthreshold remaining bioactivity, stimulated an unexpectedly high level of receptor-mediated second messenger signaling. Quantitative comparison of observed functions with those of corresponding unlabeled peptides suggested that the bioactivity of each radioligand had been largely conserved despite the radioactive decay of the iodine label. Consistent with an apparent absence of decay catastrophe, we noted that the specific radioactivity, when determined immediately following peptide iodination, was close to the theoretical maximum but exponentially decreased over time. These findings raise the possibility that attachment of a Bolton-Hunter conjugate may shield labeled peptides from radiation-induced damage, a scenario that should be considered when performing radioligand binding experiments.

Animals↗
PubMed1997

Role of superoxide anions in changes of endothelial vasoactive response during acute hyperglycemia.

The effects of acute hyperglycemia on endothelial Ca2+ signaling, formation of endothelium-derived relaxing factor (EDRF) and bioactivity of EDRF were investigated. Hyperglycemia increased 2,5-tert-butyl-1,4-hydrochinone (BHQ)-initiated Ca2+ signaling and EDRF formation in a concentration-dependent manner. The effect of elevated D-glucose on Ca2+/EDRF response could be diminished by co-incubation with the antioxidants vitamin E, probucol, GSH, vitamin C and superoxide dismutase. Convincingly, hyperglycemic conditions yielded an increase in superoxide anion release from endothelial cells and the superoxide anion-generating mixture xanthine oxidase/hypoxanthine mimicked the effect of hyperglycemia on Ca2+/EDRF signaling. Besides an enhanced formation of the vasodilatatory NO compound EDRF, hyperglycemia enhanced NO degradation by endothelial cells and, thus, reduced bioactivity of EDRF. We suggest that vasoactivity during acute hyperglycemia depends on the superoxide anion scavenging properties of the vascular wall. In acute hyperglycemia and early stages of diabetes, radical scavenging capacity may be suitable to protect NO degradation, resulting in an enhanced vasodilation. In contrast, decreased free radical scavenging properties of the vasculature in prolonged hyperglycemia and in later stages of diabetes might promote NO degradation by an overshoot of superoxide anions, resulting in an attenuation of endothelium-dependent vasodilation.

Animals↗
PubMed2001

Mutagenicity of bay-region amino-substituted cyclopenta[a]phenanthrenes and 2- and 5-aminochrysene.

The relative mutagenic potentials of 11-amino-16,17-dihydro-15H-cyclopenta[a]phenanthrene, its 17-keto derivative, and 2- and 5-aminochrysene have been compared in Salmonella typhimurium TA98 and TA100 in the presence of a postmitochondrial liver preparation from Aroclor 1254 induced rats. The 11-amino hydrocarbon is a very weak mutagen (0.27 revertants/nmol), whereas the 11-amino-17-ketone is much more active (129 revertants/nmol). 2-Aminochrysene is the most mutagenic arylamine ( approximately 500 revertants/nmol) among these compounds, but its 5-amino isomer is much less active (0.9 revertants/nmol). Possible reasons for these marked differences are suggested. Use of TA98 with over-expressing O-acetyltransferase (YG 1024) and deficient in this enzyme (TA98/l,8-DNP(6)) with the 11-amino-17-ketone and with 5-aminochrysene clearly indicates the importance of this enzyme in their bioactivation, implying oxidation of the amino group to the hydroxylamine in both these compounds.

Androstenes↗
PubMed1999

Novel antitumor agents from higher plants.

This review article describes research on cytotoxic natural products isolated from plant sources, primarily preclinical lead identification and structural modification studies performed in the Natural Products Laboratory of Dr. K. H. Lee. As a result of this work, more than 100 new cytotoxic antitumor compounds and their synthetic analogs have shown confirmed activity in NCI's in vitro human tumor cell lines bioassay and are of current interest to NCI for further in vivo evaluation. A significant and ongoing project involves novel antitumor analogs related to podophyllotoxin and etoposide, and has led to a potent derivative designated GL331 (17). This compound is currently in Phase IIa clinical trials and shows promise as an anticancer drug, especially for drug-resistant cancers. Bioactivity-directed fractionation and isolation of medicinal herbs (primarily herbs of Chinese origin) have also led to many classes of cytotoxic compounds including polyphenolic compounds, sesquiterpene lactones, lignans, quassinoids, triterpene glucosides, flavonoids, colchicine derivatives, and quinone derivatives.

Animals↗
PubMed2002

Bioactive polysaccharides from traditional Chinese medicine herbs as anticancer adjuvants.

PURPOSE OF STUDY: To review the nature, extent, bioactivities, and clinical application of polysaccharides in Traditional Chinese Medicine (TCM) especially as adjuvants in cancer treatment. METHODOLOGY: Literature review. FINDINGS: Many fungal- and plant-derived bioactive polysaccharides with a broad range of immunomodulatory activities are found in TCM. Some such polysaccharides have been developed into drugs and show clinical efficacy in controlled trials while the majority of such compounds remain as nutraceuticals with only preliminary research. Such polysaccharides are generally nontoxic and possess other bioactivities such as inducing differentiation, stimulating hematopoiesis, antimetastasis, and antiangiogenesis, which make them ideal adjuvants in modern cancer therapy. CONCLUSION: Bioactive polysaccharides occur extensively in TCM herbs and are the basis of potentially useful application of TCM as an adjuvant in cancer therapies.

Adjuvants, Immunologic↗
PubMed2001

Analgesic activity and opioid receptor selectivity of stereoisomers of ohmefentanyl isothiocyanate.

Ohmefentanyl is a very potent and highly selective agonist for mu-opioid receptors. We now study analgesia, in vitro activity and opioid receptor affinity of the stereoisomers of ohmefentanyl isothiocyanate. We found that some isomers of ohmefentanyl isothiocyanate had a potent analgesic effect and that all isomers except (3R,4S,2'S)-ohmefentanyl isothiocyanate had a more potent inhibitory action on the electrically evoked contractions of mouse vas deferens than of guinea pig ileum. The inhibitory actions could be antagonized by naloxone. However, compared with the activity of the corresponding stereoisomers of ohmefentanyl, these ohmefentanyl isothiocyanates had significantly reduced analgesia and in vitro activity. They also inhibited the binding of [3H]DPDPE ([D-Pen(2),D-Pen(5)]enkephalin) and [3H]DAGO ([D-Ala(2),Mephe(4),Gly-ol(5)]enkephalin) to opioid receptors in mouse brain membranes. The inhibitory effect of stereoisomers of ohmefentanyl isothiocyanate at mu-opioid receptors was markedly lower than that of their parent compounds. The affinity of stereoisomers of ohmefentanyl isothiocyanate for delta-opioid receptors was, however, greater than or equal to that of their corresponding stereoisomers of ohmefentanyl. The results showed that the introduction of an isothiocyanato group into the phenyl ring in position-1 of ohmefentanyl reduced bioactivity and affinity to mu-opioid receptors but that the selectivity of these compounds for delta-opioid receptors was enhanced. Isomer (3R,4S,2'R)-ohmefentanyl isothiocyanate showed highest selectivity for delta-opioid receptors (K(i)(mu)/K(i)(delta)=13.6) and potent analgesic activity (ED(50)=0.25 mg/kg).

Analgesics, Opioid↗
PubMed2006

Medicinal chemistry of N-acylhydrazones: new lead-compounds of analgesic, antiinflammatory and antithrombotic drugs.

In this article we provide an overview on the medicinal chemistry of new bioactive N-acylhydrazone (NAH) derivatives designed through the structural optimization of N-arylhydrazone precursors, originally planned by molecular hybridization of two known 5-lipoxygenase inhibitors, i.e. CBS-1108 and BW-755c. The analgesic, antiedematogenic and platelet anti-aggregating profile of several isosteric NAH compounds was investigated by using classical in vivo and ex-vivo pharmacological assays, which allowed the identification of new potent centrally and peripherically-acting analgesic leads, new antiinflammatory agents and new antithrombotic prototypes. During this study, dozens of active NAH compounds were discovered, clarifying the structure-activity relationships for this series of derivatives and indicating the pharmacophoric character of the N-acylhydrazone moiety for its biological profile.

Analgesics↗
PubMed1998

New azole antifungals. 2. Synthesis and antifungal activity of heterocyclecarboxamide derivatives of 3-amino-2-aryl-1-azolyl-2-butanol.

A series of 92 azole antifungals containing an amido alcohol unit was synthesized. The nature and substitution of the amide portion was systematically modified in search of improved antifungal activity, especially against filamentous fungi. The compounds were tested in vitro against a variety of clinically important pathogens and in vivo (po) in a murine candidosis model. Thiazole and thiophene carboxamides carrying both a substituted phenyl ring and a small alkyl group were best suited for activity against filamentous fungi. In a subset of these compounds, the amide portion was conformationally locked by means of a pyrimidone ring and it was proven that only an orthogonal orientation of the phenyl ring yields bioactive products. A tendency to display long plasma elimination half-lives was observed in both series. Two compounds, 74 and 107, representative of the open and cyclic amides, respectively, were chosen for further studies, based on their excellent activity in in vivo murine models of candidosis and aspergillosis. This work describes the SARs found within this series. The next paper displays the results obtained in a related series of compounds, the quinazolinones.

Animals↗
PubMed1997

Enantiomers of cis- and trans-3-(4-propyl-cyclopent-2-enyl) propyl acetate. A study on the bioactive conformation and chiral recognition of a moth sex pheromone component.

The enantiomers of cis- and trans-3-(4-propyl-cyclopent-2-enyl) propyl acetate, which are conformationally constrained analogues of (Z)-5-decenyl acetate (1), a sex pheromone component of the turnip moth, Agrotis segetum, have been synthesized and tested using the electrophysiological single-sensillum technique. The analogues mimic a cisoid and transoid conformation of 1, respectively. In addition, the enantiomers of each of the cis- and trans-isomers are conformationally constrained analogues of enantiomeric cisoid and transoid conformations of 1. Thus, the compounds prepared and tested are well suited to investigate the nature of the bioactive conformation of the natural pheromone component 1 and the chiral sense of its interaction with the receptor. Electrophysiological single-sensillum recordings show that the activity of the most active cis-isomer, which has a (1S,4R)-configuration, is more than two orders of magnitude higher than that of the most active trans-isomer. Furthermore, the (1S,4R)-isomer is at least 100 times more active than its enantiomer. These results strongly support a previously proposed cisoid bioactive conformation of 1. Furthermore, the (1S,4R)-configuration of most active stereoisomer identifies the chiral sense of the interaction between the natural pheromone component 1 and its receptor.

Acetates↗
PubMed2006

Activity-guided isolation of an antiandrogenic compound of Pygeum africanum.

Inactivation of the androgen receptor (AR) through androgen ablation and treatment with antiandrogens is a major goal in the therapy for prostate hyperplasia and prostate cancer. Bioactivity-directed fractionation of a selective dichloromethane extract from the stem bark of Pygeum africanum led to the isolation of the antiandrogenic compound atraric acid. Its activity was examined by an androgen receptor responsive reporter gene assay. For lead structure optimization we transformed the natural occurring compound atraric acid into its ethyl, N-propyl and N-butyl esters and their antiandrogenic activities were examined as well. In addition, benzoic acid was isolated. The structures of all compounds were determined and characterized by means of 1H- and 13C-NMR, HR-EI-mass, IR and UV spectroscopy.

Androgen Antagonists↗
PubMed2006

Binding interaction of quercetin-3-beta-galactoside and its synthetic derivatives with SARS-CoV 3CL(pro): structure-activity relationship studies reveal salient pharmacophore features.

The 3C-like protease (3CL(pro)) of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) is one of the most promising targets for discovery of drugs against SARS, because of its critical role in the viral life cycle. In this study, a natural compound called quercetin-3-beta-galactoside was identified as an inhibitor of the protease by molecular docking, SPR/FRET-based bioassays, and mutagenesis studies. Both molecular modeling and Q189A mutation revealed that Gln189 plays a key role in the binding. Furthermore, experimental evidence showed that the secondary structure and enzymatic activity of SARS-CoV 3CL(pro) were not affected by the Q189A mutation. With the help of molecular modeling, eight new derivatives of the natural product were designed and synthesized. Bioassay results reveal salient features of the structure-activity relationship of the new compounds: (1) removal of the 7-hydroxy group of the quercetin moiety decreases the bioactivity of the derivatives; (2) acetoxylation of the sugar moiety abolishes inhibitor action; (3) introduction of a large sugar substituent on 7-hydroxy of quercetin can be tolerated; (4) replacement of the galactose moiety with other sugars does not affect inhibitor potency. This study not only reveals a new class of compounds as potential drug leads against the SARS virus, but also provides a solid understanding of the mechanism of inhibition against the target enzyme.

Binding Sites↗
PubMed2001

Cellular and molecular basis for species, sex and tissue differences in 1,3-butadiene metabolism.

Species differences in 1,3-butadiene (BD) bioactivation and detoxication have been implicated in the greater sensitivity of mice to the carcinogenic effects of BD compared to rats, but the molecular basis for species differences in BD metabolism is not well understood. Previous and recent work conducted in this laboratory has examined the relative rates of BD oxidation to epoxybutene (EB) in male and female B6C3F1 mouse tissues, characterized the major cytochrome P450 enzymes involved in BD bioactivation in these tissues, and determined the potential utility of the freshly isolated hepatocyte model to investigate species differences in metabolism of BD and related compounds. Collectively, the results suggest a role for P450s 2E1, 2A5, and 4B1 in sex and tissue differences in BD bioactivation in the mouse. When coordinated metabolism of EB was investigated in male B6C3F1 mouse and Sprague-Dawley rat hepatocytes, the hepatocytes from both species were found to catalyze EB oxidation to meso- and (+/-)-diepoxybutane (DEB), EB hydrolysis to 3-butene-1,2-diol (BDD), and EB conjugation to form GSH conjugates (GSEB). The metabolite area under the curve (AUC) exhibited dependence on the EB concentration used. However, the EB activation/detoxication ratios with the mouse hepatocytes were much higher than the ratios obtained with the rat hepatocytes. These results illustrate the potential utility of the hepatocyte model for estimating flux through competing metabolic pathways and predicting in-vivo metabolism of EB. Collectively, the results may allow a better understanding of the molecular and kinetic basis of species differences in BD metabolism and may lead to a more accurate assessment of human risk.

Animals↗