Solid-phase synthesis of polyfunctionalized natural products: application to usnic acid, a bioactive lichen compound.
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Anti-Bacterial Agents↗
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Frontal affinity chromatography with MS detection of EphB2 tyrosine kinase receptor. 2. Identification of small-molecule inhibitors via coupling with virtual screening.
We have integrated two complementary methods, high-throughput virtual screening with a "high-content" wet screening technique based on frontal affinity chromatography with mass spectrometry detection (FAC-MS), for identification of hits against the erythropoietin-producing hepatocellular B2 (EphB2) receptor tyrosine kinase domain. Both an EphB2-directed virtual screen combining docking and scoring and a kinase-directed pharmacophore search strategy were used to identify a compound set enriched in bioactive compounds against EphB2. The coupling of virtual screening methodologies with FAC-MS is a unique hybrid approach that can be used to increase the efficacy of both hit discovery and optimization efforts in drug discovery and has successfully identified hits, in particular 19a (36% shift, IC(50) = 5.2 microM, K(d) = 3.3 microM), as inhibitors for EphB2, a potential cancer target.
Antineoplastic Agents↗
Isolation and biochemical characterization of a new topoisomerase I inhibitor from Ocotea leucoxylon.
In a continuation of our search for potential tumor inhibitors from plants, we found that a crude extract from Ocotea leucoxylon showed selective activity typical of inhibitors of the enzyme topoisomerase I in a yeast assay for DNA-damaging agents. Using a bioassay-directed fractionation approach, the major bioactive compound was isolated and identified as the known aporphine alkaloid dicentrinone (4); the inactive alkaloid dicentrine (3) was also isolated. Compound 4 showed selective bioactivity against the rad52 repair-deficient yeast strain RS322 (IC(12) 49 microg/mL) and was inactive against the rad52- and topo1-deficient strain RS321 (IC(12) > 2000 microg/mL) and against the repair-proficient strain RJ03 (IC(12) > 2000 microg/mL). Biochemical studies with recombinant human topoisomerase I indicated that dicentrinone (4) is an inhibitor of the human enzyme. Colony formation studies suggest that it is weakly cytotoxic, but that its mechanism of toxicity differs from that of camptothecin and its derivatives.
Aporphines↗
New and bioactive aromatic compounds from Zanthoxylum zanthoxyloides.
In the course of a study of medicinal plants from Mali, the root bark of Zanthoxylum zanthoxyloides Lam. (Rutaceae) was investigated. The root bark of this plant is used as a toothbrush by West African people. Phytochemical investigation of the MeOH extract of Zanthoxylum zanthoxyloides Lam. (Rutaceae) led to the isolation of different biologically active compounds. The separation of acetylcholinesterase inhibitors was performed by centrifugal partition chromatography (CPC). The fractions were monitored by direct TLC bioautographic assays. The bio-guided isolation led to the isolation of a new peroxide derivative. In addition, LC/UV/MS analysis performed on the crude MeOH extract allowed on-line identification of some known compounds. The structures of the isolated compounds were elucidated by classical spectroscopic methods including UV, NMR, MS and HR-MS.
Antifungal Agents↗
New pharmaceutical microemulsion system for encapsulation and delivery of diospyrin, a plant-derived bioactive quinonoid compound.
A new vegetable oil based oil-in-water microemulsion is developed and characterized as a prospective delivery system for in vivo application A particular weight percent composition 5/30/65 (clove oil/Tween-20/water) was selected (V1) from the clear oil-in-water zone of the pseudoternary phase diagram comprising clove oil, polyoxyethylene sorbitan monolaurate (Tween-20), and water. Two modifications of V1, (V2 and V3) were prepared by addition of dipalmitoyl phosphatidyl choline (DPPC), and a mixture of DPPC and cholesterol, respectively. A model drug diospyrin (a plantderived quinonoid compound) was encapsulated in the dispersed clove oil droplets of the three systems and designated as DV1, DV2, and DV3, respectively. The size of the dispersed clove oil droplets ranged between 9-20 nm as determined by dynamic light scattering. The stability of the vehicles, before and after encapsulation, was assessed under varying conditions of time and temperature and was found to be stable for 1 year and over a temperature range of 4-40 degrees C. The ultraviolet-visible spectrum of diospyrin after encapsulation in the compartmentalized medium remained almost identical to that dissolved in chloroform. The single-dose acute toxicity of V1 and DV1 was assessed in vivo by carrying out survival study and enzyme assay in Swiss Albino mice. The vehicle was safe at a volume of 0.05 ml when injected intraperitoneally into the mice.
1,2-Dipalmitoylphosphatidylcholine↗
Developing synthetic methods for bioactive phosphorus compounds using H-phosphonate chemistry: a progress report.
In this paper a short account of our recent research concerning the development of new synthetic methods and reagents for the preparation of nucleotides and their analogues, is given.
Models, Molecular↗
Developing synthetic methods for bioactive phosphorus compounds using H-phosphonate chemistry: a progress report.
In this paper a short account of our recent basic studies aiming toward development of new synthetic methods for the preparation of nucleotide analogues using H-phosphonate chemistry is presented.
Models, Chemical↗
Neural network methods for identification and optimization of quantum mechanical features needed for bioactivity.
This paper presents a new approach to the discovery and design of bioactive compounds. The focus of this application will be on the analysis of enzymatic inhibitors. At present the discovery of enzymatic inhibitors for therapeutic use is often accomplished through random searches. The first phase of discovery is a random search through a large pre-fabricated chemical library. Many molecules are tested with refined enzyme for signs of inhibition. Once a group of lead compounds have been discovered the chemical intuition of biochemists is used to find structurally related compounds that are more effective. This step requires new molecules to be conceived and synthesized, and it is the most time-consuming and expensive step. The development of computational and theoretical methods for prediction of the molecular structure that would bind most tightly prior to synthesis and testing, would facilitate the design of novel inhibitors. In the past, our work has focused on solving the problem of predicting the bioactivity of a molecule prior to synthesis. We used a neural network trained with the bioactivity of known compounds to predict the bioactivity of unknown compounds. In our current work, we use a separate neural network in conjunction with a trained neural network in an attempt to gain insight as to how to modify existing compounds and increase their bioactivity.
Enzyme Inhibitors↗
Bioactive berry compounds-novel tools against human pathogens.
Berry fruits are rich sources of bioactive compounds, such as phenolics and organic acids, which have antimicrobial activities against human pathogens. Among different berries and berry phenolics, cranberry, cloudberry, raspberry, strawberry and bilberry especially possess clear antimicrobial effects against, e.g. Salmonella and Staphylococcus. Complex phenolic polymers, like ellagitannins, are strong antibacterial agents present in cloudberry and raspberry. Several mechanisms of action in the growth inhibition of bacteria are involved, such as destabilisation of cytoplasmic membrane, permeabilisation of plasma membrane, inhibition of extracellular microbial enzymes, direct actions on microbial metabolism and deprivation of the substrates required for microbial growth. Antimicrobial activity of berries may also be related to antiadherence of bacteria to epithelial cells, which is a prerequisite for colonisation and infection of many pathogens. Antimicrobial berry compounds may have important applications in the future as natural antimicrobial agents for food industry as well as for medicine. Some of the novel approaches are discussed.
Anti-Bacterial Agents↗
Snakebite ethnopharmacopoeia of eastern Nicaragua.
Results of an ethnopharmacognostic study of snakebite treatments in eastern Nicaragua are presented. Data and specimens were collected during several years of field studies. Field work consisted of plant collecting trips and interviews of snakedoctors. The annual mortality from snakebites in eastern Nicaragua is about 25% and most bites are caused by the fer-de-lance (Bothrops asper). The vascular flora of the region is estimated at 2500 species of which 435 have medicinal application including 81 that are used in snakebite treatment. The majority of species used in snakebite cures are flowering plants, 76% dicots and 20% monocots, and 80% are obtained from the second-growth forest. About half the species are herbs. Leaves are the most frequently utilized plant part. Most herbal remedies are prepared as decoctions and are administered orally. Remedies are mostly prepared with native wild species, but some are introduced domesticates, derived from either the American or Old World Tropics. All the species used contain at least one bioactive compound, and most of these bioactives have been shown in other studies to have pharmacological effects. The use of species in snakebite treatments does not necessarily imply efficacy, but it does give a limited list of species that can be studied pharmacologically for possible bioactive effects. Studies like this one are also important because they document traditional practices and species utilized for the people of the region studied as well.
Ethnopharmacology↗
Forward chemical genetics: progress and obstacles on the path to a new pharmacopoeia.
Forward chemical genetics is a new method to systematize the discovery and use of small molecules as tools for basic biological research. This approach requires three basic components: a library of compounds; an assay, in which the library is screened for a cellular or organismal phenotype; and a method to trace an active compound to its biological target. Bioactive compounds have traditionally been isolated from natural product extracts, although 'diversity-oriented synthesis' and commercial compound collections are gaining in prominence. New techniques, such as image-based screening and the cytoblot method, have increased the throughput of phenotypic assays. Strategies are also being developed to streamline target identification using molecular biological approaches.
Drug Evaluation, Preclinical↗
Flavonoids from the stem of Eriophorum scheuchzeri.
Activity-guided isolation of antifungal, antibacterial, and antioxidant compounds from the dichloromethane extract of the aerial parts of Eriophorum scheuchzeri led to the isolation of eight flavonoids. Three isoflavones and one flavanone are new natural compounds. The isolation of the bioactive compounds was performed by centrifugal partition chromatography. Fractions and pure compounds were monitored by a direct TLC bioautographic assay. Their structures were elucidated by spectroscopic and chemical methods.
Anti-Bacterial Agents↗
Design and synthesis of beta-peptides with biological activity.
beta-Peptides have been used as a platform for developing bioactive compounds with various types of bioactivity such as antimicrobial activity, cholesterol absorption inhibition, somatostatin receptor agonist, and hDM2 inhibition. These bioactive beta-peptides have been designed based on bioactive alpha-peptides. Three main strategies have been used to design bioactive beta-peptides: direct conversion of alpha-peptide sequences into beta-peptide sequences, placement of side chains to provide desirable distribution of physicochemical properties, and the grafting of proteinaceous side chains critical for bioactivity onto beta-peptide structures. This chapter briefly discusses the various strategies employed to design bioactive beta-peptides, followed by protocols for the synthesis of N-alpha-fluorenylmethyloxycarbonyl (Fmoc)-protected beta3-amino acids from Fmoc-protected alpha-amino acids, and synthesis of beta-peptides by solid phase methods using Fmoc-based chemistry.
Amino Acids↗
Functional properties of edible mushrooms.
Edible mushrooms such as shiitake may have important salutary effects on health or even in treating disease. A mushroom characteristically contains many different bioactive compounds with diverse biological activity, and the content and bioactivity of these compounds depend on how the mushroom is prepared and consumed. It is estimated that approximately 50% of the annual 5 million metric tons of cultivated edible mushrooms contain functional "nutraceutical" or medicinal properties. In order of decreasing cultivated tonnage, Lentinus (shiitake), Pleurotus (oyster), Auricularia (mu-er), Flammulina (enokitake), Tremella (yin-er), Hericium, and Grifola (maitake) mushrooms have various degrees of immunomodulatory, lipid-lowering, antitumor, and other beneficial or therapeutic health effects without any significant toxicity. Although the data for this functional food class are not as strong as those for other functional foods such as cruciferous vegetables, because of their potential usefulness in preventing or treating serious health conditions such as cancer, acquired immune deficiency syndrome (AIDS), and hypercholesterolemia, functional mushrooms deserve further serious investigation. Additionally, there is a need for epidemiological evidence of the role of this functional food class.
Food↗
A standardized protocol for assessing regulators of pigmentation.
Varied effects of chemical or biological compounds on mammalian pigmentation have been reported by many groups, but to date, no standardized method has established necessary and/or optimal parameters for testing such agents. A standardized method has been developed to screen compounds with potential effects on pigmentation. The protocol comprises basic parameters to analyze melanogenic effects and allows for further characterization of candidate compounds, providing important insights into their mechanism of action. In this protocol (termed STOPR, for standardized testing of pigmentation regulators), compounds are initially screened using purified tyrosinase and are then tested on melanocytes in culture. After treatment of melanocytes with potentially bioactive compounds, cell proliferation and viability, total melanin accumulated, and melanogenic potential are measured. This protocol is an important first step in characterizing chemical regulation of effects on melanogenesis. When bioactive candidate compounds are identified, testing may proceed for pharmacological or otherwise commercial applications in coculture and/or organ culture models followed by in vivo testing. As an application of this method, results for compounds known to stimulate and/or inhibit melanogenesis (including arbutin, hydroquinone, kojic acid, melanocyte-stimulating hormone, and thymidine dimers) as well as some commercial skin whiteners are reported.
Animals↗
Enzymes functional in the syntheses of leukotrienes and related compounds.
1. Leukotrienes (LT) constitute a family of bioactive compounds mainly involved in inflammatory and immunological responses. 2. LTs are produced via an unstable intermediate, LTA4 which is synthesized by the action of arachidonate 5-lipoxygenase, a calcium-dependent enzyme. 3. LTA4 is converted to either LTB4 by cytosolic LTA4 hydrolase or to LTC4 by LTC4 synthase present in the microsomal fraction. 4. Three enzymes (5-lipoxygenase, LTA4 hydrolase and LTC4 synthase) were purified, and molecular and kinetic properties have been extensively investigated. 5. The cDNA of LTA4 hydrolase was recently isolated, and the primary structure was fully determined in our laboratory. 6. I report herein recent progress in studies on arachidonic acid metabolism, with the focus primarily on enzymes linked to the 5-lipoxygenase pathway.
Animals↗
[Semi-synthesis of derivatives with C-3' and C-4' trans-configuration from (+)-praeruptorin A].
AIM: In order to compare the calcium antagonist activity between the derivatives of (+)-praeruptorin A with C-3' and C-4' cis-configuration and trans-configuration, and to look for new active compounds, some derivatives with C-3', C-4' trans-configuration of (+)-praeruptorin A were semi-synthsized. METHODS: (+)-Praeruptorin A was isolated from the root of Peucedanum praeruptorum. Basic hydrolysis of (+)-praeruptorin A was carried out. From the alkaline hydrolysis product (2), eight new products (5-12) with C-3', C-4' trans-configuration were semi-synthsized whose C-3' was linked to angeloyloxy and C-4' was linked to various acyloxy, using respective acids as acylating agents, DCC as a dehydrant, DMAP as catalyst. From the alkaline hydrolysis product (4), five new products (13-17) with C-3', C-4' trans-configuration were obtained whose C-3', C-4' is linked to various same acyloxys, using respective acids as acylating agents, DCC as dehydrant, DMAP as catalyst. Also from the alkaline hydrolysis product (4), using respective acyl chlorides as acylating agents, anhydrous dichloromethane containing minor pyridine as a solvent, the improved Schotten-Baumann reactions were carried out, two new products (18, 20) with C-3', C-4' trans-configuration were obtained whose only C-3' linked to acyloxy and two other new products (19, 21) with C-3', C-4' trans-configuration were obtained whose C-3' and C-4' linked two acyloxys. The structures of all the products were elucidated by spectral analyses including IR, 1HNMR and EIMS. The calcium antagonist activity of all of the products were tested by inhibition of the systole of rat artery ring. RESULTS: Seventeen compounds with C-3', C-4' trans-configuration were semi-synthesized from (+)-praeruptorin A for the first time and their calcium antagonist activity were evaluated. CONCLUSION: All of the derivatives were new compounds. Bioactivity assay indicated that some new compounds with C-3', C-4' trans-configuration showed obvious calcium antagonist activity, but they are not as strong as (+)-praeruptorin A. The activity of some products was shown to be similar to that of the derivatives with C-3', C-4' cis-configuration for the first time.
Animals↗
Identification of potential genomic biomarkers of hepatotoxicity caused by reactive metabolites of N-methylformamide: Application of stable isotope labeled compounds in toxicogenomic studies.
The inability to predict if a metabolically bioactivated compound will cause toxicity in later stages of drug development or post-marketing is of serious concern. One approach for improving the predictive success of compound toxicity has been to compare the gene expression profile in preclinical models dosed with novel compounds to a gene expression database generated from compounds with known toxicity. While this guilt-by-association approach can be useful, it is often difficult to elucidate gene expression changes that may be related to the generation of reactive metabolites. In an effort to address this issue, we compared the gene expression profiles obtained from animals treated with a soft-electrophile-producing hepatotoxic compound against corresponding deuterium labeled analogues resistant to metabolic processing. Our aim was to identify a subset of potential biomarker genes for hepatotoxicity caused by soft-electrophile-producing compounds. The current study utilized a known hepatotoxic compound N-methylformamide (NMF) and its two analogues labeled with deuterium at different positions to block metabolic oxidation at the formyl (d(1)) and methyl (d(3)) moieties. Groups of mice were dosed with each compound, and their livers were harvested at different time intervals. RNA was prepared and analyzed on Affymetrix GeneChip arrays. RNA transcripts showing statistically significant changes were identified, and selected changes were confirmed using TaqMan RT-PCR. Serum clinical chemistry and histopathologic evaluations were performed on selected samples as well. The data set generated from the different groups of animals enabled us to determine which gene expression changes were attributed to the bioactivating pathway. We were able to selectively modulate the metabolism of NMF by labeling various positions of the molecule with a stable isotope, allowing us to monitor gene changes specifically due to a particular metabolic pathway. Two groups of genes were identified, which were associated with the metabolism of a certain part of the NMF molecule. The metabolic pathway leading to the production of reactive methyl isocyanate resulted in distinct expression patterns that correlated with histopathologic findings. There was a clear correlation between the expression of certain genes involved in the cell cycle/apoptosis and inflammatory pathways and the presence of reactive metabolite. These genes may serve as potential genomic biomarkers of hepatotoxicity induced by soft-electrophile-producing compounds. However, the robustness of these potential genomic biomarkers will need to be validated using other hepatotoxicants (both soft- and hard-electrophile-producing agents) and compounds known to cause idiosyncratic liver toxicity before being adopted into the drug discovery screening process.
Animals↗