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Recent progress in separation techniques has enabled us to work with water-soluble components which, more often than not, are responsible for biological activities found in marine organisms. Isolation techniques and chemical and biological aspects of water-soluble marine natural products will be discussed with some representative examples.
The bioactivity of Myoporum bontioides extracts to Plutella xylostella was studied with IIPC as evaluated index. The results showed that petroleum ether and chloroform extracts had a higher activity than ethyl acetate and alcohol extracts. At 0.01 gDW x ml(-1), the ODR of petroleum ether and chloroform extracts was 84.69% and 79.90%, and 76.47% and 45.70% after treated 1d and 3d, while the IIPC was 0.1565 and 0.2055, respectively. Provided with a higher concentration of 0.05 gDW x ml(-1), the ODR was 88.52% and 72.25%, and 87.33%, 58.37%, while the IIPC was 0.1125 and 0.2620, respectively. From the chloroform extract of Myopdrum Bontioides, three flavonoids, 2, 3-dihydro-5, 7-dihydroxy-2-phenyl-4H-1-Benzopyran-4-one (I), 3, 5, 7-trihydroxy-2-phenyl-4H-1-Benzopyran-4-one (II) and 5, 7-dihydroxy-3-methoxy-2-(4-methoxyphenyl)-4H-1-Benzopyran-4-one (III), were isolated, and their structure were identified based on the analyses of physical and spectrum data. Among these compounds, (II) had a better bioactivity to Plutella xylostella.
Metabolic activation of nitrogenous compounds by the cytochrome P-450 system is a highly complex process. Inherent substrate factors, such as basicity, electronic state, lipophilicity, and conformation control binding of the diverse classes of amines to cytochrome P-450. Accommodation of these compounds in the enzyme cavity and proper orientation of the molecules are governed by intrinsic properties of the peptide structure of cytochrome P-450, which may be subject to modification by the action of effectors. On the membrane level, phospholipid might have some impact on substrate binding. On the other hand, bound amine substrate is beneficial to the productive interaction of the electron transport chains with the terminal acceptor, improving economy of the system. Certain amines appear to regulate O2 association with cytochrome P-450 and stabilize the various oxy species formed. Considering the selective prerequisites for oxidative attack by cytochrome P-450 at vulnerable nitrogen centers, many cytotoxic amines belonging to the category of relatively rigid, planar molecules undergo N-oxidative activation by the cytochrome P-450IA subfamily, while more bulky amines with flexible conformation are N-oxygenated preferentially by phenobarbital-inducible cytochromes P-450. Small differences in protein structure between the various cytochrome P-450 subforms might serve to stabilize aminium radicals to permit oxygen rebound. Collectively, the selective regulatory mechanisms operative in the bioactivation of nitrogen-containing compounds appear to be determined largely by the type of substrate used and the isozyme involved in catalysis. With respect to the latter, the interplay of the multiple cytochromes P-450 in the various organs of animal species thus serves to rationalize the differences in the particular selectivities for amine substrates. These are responsible for the mode and/or extent to which activation of nitrogenous compounds, including promutagens and procarcinogens, occurs, and this may explain the tissue-specific response to the tumorigenic action of these agents.
Metabolism and bioactivation of fluoroanilines was studied both in vitro in microsomal systems and in vivo. 4-Fluoroaniline and pentafluoroaniline and their non-para fluorinated analogues were used as the model compounds. Special attention was focussed on bioactivation to reactive benzoquinoneimines. Cytochrome P-450 dependent monooxygenation at a non-fluorinated para position in (fluoro)aniline derivatives proceeds by formation of the para hydroxylated derivative as the primary metabolite. Monooxygenation at a fluorinated para position in an aniline derivative, however, proceeds by formation of fluoride anion and the reactive benzoquinoneimine as primary reaction products. Thus, for fluoroanilines with a fluorine substituent at the para position bioactivation to the reactive benzoquinoneimine can be a direct result of the cytochrome P-450 dependent conversion. In systems containing NAD(P)H and/or other reducing equivalents part of the benzoquinoneimine can be chemically reduced to give the corresponding 4-hydroxyaniline. In vivo this reduced form of the metabolite can be sulphated or glucuronidated and excreted into urine. The results obtained point to increased chances of bioactivation for aniline derivatives with a fluorinated para position as compared to their non-para fluorinated analogues, both in vitro but also in vivo.
Bioactivity-directed fractionation of the fermentation broth and mycelium of the coprophilous fungus Guanomyces polythrix led to the isolation of several phytotoxic compounds, including five new naphthopyranone derivatives (1-5). In addition, rubrofusarin B, emodin, citrinin, and 4-hydroxybenzoic acid methyl ester were obtained. The structures of the new compounds were established by spectral and chiroptical methods. The isolates caused significant inhibition of radicle growth of two weed seedlings (Amaranthus hypochondriacus and Echinochloa crusgalli) and interacted with both spinach and bovine brain calmodulins.
Seven new compounds (1-6 and 10) with a unique carbon skeleton have been isolated from the sponge Hamigera tarangaensis, and the structure of a previously reported metabolite has been revised from 12 to 8. The structures have been assigned from extensive NMR examination. Compounds 3-6 showed moderate in-vitro cytotoxicity against P-388, while 3 showed 100% in-vitro virus inhibition against both the Herpes and Polio viruses, with only slight cytotoxicity.
Suramin and suramin analogues strongly inhibit both nucleotide interaction with the nucleotide-binding site of granulocyte-macrophage colony-stimulating factor (GM-CSF) and bioactivity of the molecule as assessed by competition photoaffinity labeling and cell proliferation assay, respectively. The half-maximal inhibition of cell proliferation by suramin occurs at 68 +/- 2.5 microM; three suramin analogues achieved comparable activity. The degree of competitive inhibition of nucleotide-binding by these compounds and the inhibition of GM-CSF bioactivity are correlated such that the compounds show similar rank-order by both of these methods. The strong interaction of suramin and related compounds with the nucleotide-binding site may mimic nucleotide-mediated inhibition of GM-CSF bioactivity and may be an important mechanism by which suramin acts as a pharmacological anti-growth factor agent.
The genus of filamentous cyanobacteria, Lyngbya, has been found to be a rich source of bioactive metabolites. However, identification of such compounds from Lyngbya has largely focused on a few marine representatives. Here, we report on the pharmacology and toxicology of pahayokolide A from a freshwater isolate, Lyngbya sp. strain 15-2, from the Florida Everglades. Specifically, we investigated inhibition of microbial representatives and mammalian cell lines, as well as toxicity of the compound to both invertebrate and vertebrate models. Pahayokolide A inhibited representatives of Bacillus, as well as the yeast, Saccharomyces cerevisiae. Interestingly, the compound also inhibited several representatives of green algae that were also isolated from the Everglades. Pahayokolide A was shown to inhibit a number of cancer cell lines over a range of concentrations (IC50 varied from 2.13 to 44.57 microM) depending on the cell-type. When tested against brine shrimp, pahayokolide was only marginally toxic at the highest concentrations tested (1 mg/mL). The compound was, however, acutely toxic to zebrafish embryos (LC50=2.15 microM). Possible biomedical and environmental health aspects of the pahayokolides remain to be investigated; however, the identification of bioactive metabolites such as these demonstrates the potential of the Florida Everglades as source of new toxins and drugs.
Synthetic lipid A analogs, beta(1-6)glucosamine disaccharide 1,4'-bisphosphates, which possesses four tetradecanoyl groups at the 2- and 2'-amino, and 3- and 3'-hydroxyl groups (LA-17-PP), and each two of the (R)-3-hydroxytetradecanoyl and tetradecanoyl groups at the 2- and 2'-amino and 3- and 3'-hydroxyl groups, respectively (LA-18-PP), were far less endotoxic than synthetic (506, LA-15-PP) and bacterial Escherichia coli type lipid A's; neither compound showed any detectable lethal toxicity in chicken embryos or preparatory activity for the local Shwartzman reaction in rabbits. Also both compounds were only weakly pyrogenic and comparably less lethally toxic in galactosamine-loaded mice than the reference synthetic and bacterial lipid A's and a synthetic counterpart to biosynthetic lipid A precursor Ia (406, LA-14-PP). Nevertheless, LA-17-PP and LA-18-PP exhibited definite in vivo immunoadjuvant activity in mice, and the ability to induce a possible tumor necrosis factor and alpha/beta interferon in Mycobacterium bovis BCG and Propionibacterium acnes-primed mice, respectively, although these activities were weaker than those of the reference lipid A's. 4'-Monophosphate analogs of the above two test compounds exhibited neither endotoxic nor beneficial activities, but they showed remarkable in vitro bioactivities comparable to those of the corresponding bisphosphate compounds; the ability to activate the human complement system and the clotting enzyme cascade of horseshoe crab amoebocyte lysate, stimulatory effects on guinea pig and murine peritoneal macrophages, and murine splenocytes.
Bioactivity-guided fractionation of an alcohol extract of the soft coral Sarcophyton glaucum collected from the intertidal areas and the fringing coral reefs near Hurghada, Red Sea, Egypt resulted in the isolation of a new lactone cembrane diterpene, sarcophytolide. The structure of this compound was deduced from its spectroscopic data and by comparison of the spectral data with those of known closely related cembrane-type compounds. In antimicrobial assays, the isolated compound exhibited a good activity towards Staphylococcus aureus, Pseudomonas aeruginosa, and Saccharomyces cerevisiae. Sarcophytolide was found to display a strong cytoprotective effect against glutamate-induced neurotoxicity in primary cortical cells from rat embryos. Preincubation of the neurons with 1 or 10 microg/ml of sarcophytolide resulted in a significant increase of the percentage of viable cells from 33 +/- 4% (treatment of the cells with glutamate only) to 44 +/- 4 and 92 +/- 6%, respectively. Administration of sarcophytolide during the post-incubation period following glutamate treatment did not prevent neuronal cell death. Pretreatment of the cells with sarcophytolide for 30 min significantly suppressed the glutamate-caused increase in the intracellular Ca2+ level ([Ca2+]i). Evidence is presented that the neuroprotective effect of sarcophytolide against glutamate may be partially due to an increased expression of the proto-oncogene bcl-2. The coral secondary metabolite, sarcophytolide, might be of interest as a potential drug for treatment of neurodegenerative disorders.
UNLABELLED: Platelet and endothelial production of bioactive nitric oxide (NO) is known to be impaired in acute coronary syndromes, thus compounds that release NO are useful candidates to restore NO-vascular functions. OBJECTIVE: We have studied whether donation of NO with a novel platelet-selective S-nitrosothiol compound (LA810) at a systemic level can inhibit thrombosis elicited by damaged vessel wall (eroded and disrupted vessel wall) at hemodynamic conditions typical of patent and stenotic coronary arteries. METHODS: Thrombogenicity was measured in the porcine experimental model and assessed as platelet-thrombus formation in the ex vivo Badimon perfusion chamber. After baseline perfusions, female pigs (Large WhitexLandrace) were given intravenous infusion of LA810 or GSNO standard S-nitrosothiol during 2 h. Changes in blood pressure, heart rate and in vitro platelet aggregation were measured. RESULTS: LA810 significantly decreased thrombus formation at any degree of vascular damage and shear rate (p<0.001) without hypotensive side-effects or heart rate variations. In contrast, inhibition of thrombus formation by GSNO required high doses associated to hypotensive episodes. Platelet aggregation induced by collagen was inhibited after nitrosothiol infusion in whole blood (LA810) and platelet rich plasma (LA810 and GSNO). In addition, there was a drug-dependent rise in platelet guanosine 3',5'-cyclic monophosphate (cGMP) levels. CONCLUSIONS: This new anti-ischemic NO-donor (NOd) LA810 that inhibits platelet function without hypotensive side-effects seems a highly efficacious strategy to reduce acute thrombosis triggered by coronary artery disease.
Photorelease of bioactive molecules from inactive precursors is a very powerful tool for the study of the molecular mechanisms underlying physiological processes as diverse as ionic channel modulation, exocytosis, phototransduction, ligand-receptor interaction, and cross-bridge activity. A brief account of the methodology, available compounds, and fields of application is presented here.
Issues concerning the past and future development of medicinal herbs from Chinese medicine (CM) are addressed in this paper. In the Western world, medicinal herbs are becoming increasingly popular and important in the public and scientific communities. In contrast to their regulated status in China and other countries, herbal medicines are regarded as dietary supplements in the US. Accordingly, research must continue worldwide to identify and improve the efficacy of the active principals of herbs both singly and in combination -- from active ingredients, active fractions, and active herbal formulations. While Western medicine currently employs pure, single compounds, either natural or synthetic, CM has long used multiple combinations of compounds in the form of processed natural products, primarily medicinal herbs, to treat and relieve the symptoms of many different human diseases. CM may have fewer and less severe side effects than single pure drugs, making CM especially attractive to the consumer. In effect, CM's focus on combination therapy does serve both ancient and modern theories. However, research using modern analytical and chemical techniques is needed to ensure efficacy and safety, to provide qualitative and quantitative analyses for dietary supplements, and to develop new, effective and safe world-class drugs. Drug design is an iterative process. Bioactivity-directed fractionation and isolation identify active natural compounds from single herbs or formulations. These lead structures can be chemically modified and improved through knowledge of structure--activity relationship, mechanism of action, drug metabolism, molecular modelling and combinatorial chemistry studies. Finally, efficacy and toxicity determination as well as clinical trials can contribute to the generation of new drugs from CM. To continue the legacy of CM, as well as the worldwide uses of other medicinal herbs, continued investigation of active formulations, bioactive fractions, and isolated compounds is critical to drug development in the 21st century.
Bioactivity-guided fractionation of the root extract of Psorothamnus arborescens yielded the new isoflavone 5,7,3',4'-tetrahydroxy-2'-(3,3-dimethylallyl)isoflavone (1a) and the new 2-arylbenzofuran 2-(2'-hydroxy-4',5'-methylenedioxyphenyl)-6-methoxybenzofuran-3-carbaldehyde (2), together with seven known compounds, including three isoflavones, fremontin (3a), glycyrrhisoflavone (4a), and calycosin (5), two pterocarpans, maackiain (6) and 4-hydroxymaackiain (7), one triterpene, oleanolic acid (8), and one chalcone, isoliquiritigenin (9). In addition, the structure of the isoflavone fremontin was revised using spectroscopic and chemical methods and was assigned the new structure 3a. The isoflavone 1a and the chalcone 9 displayed leishmanicidal activity with IC50 values of 13.0 and 20.7 microM, respectively, against Leishmania donovani axenic amastigotes. Calycosin (5) exhibited selective toxicity against Trypanosoma brucei brucei (IC50 12.7 microM) compared to L. donovani amastigotes and Vero cells (IC50 100 and 159 microM, respectively). These results prompted us to test a small group of structurally related isoflavones for their antitrypanosomal activities. Genistein and 7,3',4'-trihydroxyisoflavone displayed promising activity (IC50 values 4.2 and 7.1 microM, respectively) and selectivity (IC50 versus Vero cells: 32.9 and 135 microM, respectively). These studies suggest that the isoflavone skeleton deserves further investigation as a template for novel antileishmanial and trypanocidal compounds.
OBJECTIVE: Free radical-induced oxidative stress with consequent lipid peroxidation and resultant tissue damage has been suggested as a potential mechanism of the pathogenesis of scleroderma. However, because reliable measurement of lipid peroxidation in vivo is difficult, it has not been possible to adequately examine this hypothesis. We have previously described a series of bioactive prostaglandin F2-like compounds, termed F2-isoprostanes, produced in vivo in humans by the non-cyclooxygenase, free radical-catalyzed, peroxidation of arachidonic acid and have shown them to be a reliable measure of lipid peroxidation in vivo. In the present study, we determined whether scleroderma is associated with enhanced oxidative stress. METHODS: As a measure of oxidative stress, we determined urinary concentrations of a tetranor-dicarboxylic acid metabolite of F2-isoprostanes (F2IP-M) by mass spectrometry in 8 patients with scleroderma (representing a wide spectrum of disease, including limited disease with refractory digital ulceration or pulmonary hypertension, and diffuse disease) and in 10 healthy control subjects. RESULTS: F2IP-M concentrations were significantly higher in patients with scleroderma (mean +/- SEM 3.41 +/- 0.64 ng/mg of creatinine) than in healthy controls (1.22 +/- 0.14 ng/mg of creatinine) (P = 0.002). These elevations occurred in patients with limited disease and in those with diffuse disease. CONCLUSION: The increased level of urinary F2IP-M supports the hypothesis that free radical-induced oxidative injury occurs in scleroderma and provides a biologic marker whose relationship to disease activity and disease therapy may be important. These findings may also provide a rationale for exploring whether antioxidant therapy may influence the natural course of the disease.
Astins, antitumour cyclic pentapeptides, were isolated from the Aster tataricus. Their chemical structures, consist of a 16-membered ring system containing a unique beta,gamma-dichlorinated proline [Pro(Cl)2], other non-coded amino acid residues and a cis conformation in one of the peptide bonds. The astin backbone conformation, along with the cis peptide bond in which the beta,gamma-dichlorinated proline residue is involved, was considered to play an important role in their antineoplastic activities on sarcoma 180A and P388 lymphocytic leukaemia in mice, but the scope and potential applications of this activity remain unclear. With the aim at improving our knowledge of the conformational properties influencing the bioactivity in this class of compounds, new astin-related cyclopeptides were synthesized differing from the natural products by the presence of some non-proteinogenic amino acid residues: Aib, Abu, -(S)beta3-hPhe and a peptide bond surrogate (-SO2-NH-). The analogues prepared c(-Pro-Thr-Aib-beta3-Phe-Abu-), c[Pro-Thr-Aib-(S)beta3-hPhe-Abu], c[Pro-Abu-Ser-(S)beta3-hPhe psi(CH2-SO2-NH)-Abu] and c[Pro-Thr-Aib-(S)beta3-hPhe psi(CH2-SO2-NH)-Abu] were synthesized by classical methods in solution and tested for their antitumour effect. These molecules were studied by crystal-state x-ray diffraction analysis and/or solution NMR and MD techniques.
Experimental diabetes can be produced by agents with specific toxicity for pancreatic islet B cells. This effect has been reported to be modified both in vitro and in vivo by various radical scavengers including the enzyme superoxide dismutase. Copper(II)(3,5-diisopropylsalicylate)2 is lipophilic and possesses superoxide dismutase bioactivity. Prior administration of this compound to male rats appeared to attenuate the severity of streptozotocin-induced diabetes as assessed by glycosuria and glucose tolerance. Diisopropylsalicylate, which has no superoxide dismutase activity, did not alter the severity of streptozotocin-induced diabetes. Rats treated with the copper complex, with streptozotocin or with a combination of the two agents gained 50% less weight than untreated controls, or rats treated with diisopropylsalicylate. The attenuation of diabetes by the copper-complex may represent partial protection of the B cells against streptozotocin damage, although an extrapancreatic, toxic effect cannot be ruled out.
Development of small molecular mimics of larger polypeptide ligands is an important approach to pharmacophore design. One strategy for the development of such mimics is analysis of alternative ligands that bind to the same site as the native ligand. These allow examination of the structural and chemical constraints for binding within the setting of diverse backbone geometries. The use of antireceptor antibodies as alternative ligands has allowed the development of biologically active peptides in several ligand-receptor systems. This technology has been applied to the study of interactions between human granulocyte-macrophage colony-stimulating factor (GM-CSF) and its receptor (GM-CSFR). GM-CSF is one of a family of signal-transducing cytokines and growth factors characterized by a four-helix bundle core structure. The GM-CSFR is comprised of an alpha-chain (GM-CSFR alpha) specific for GM-CSF, and a beta-chain (beta c) shared with the interleukin-3 and interleukin-5 receptors. At least two sites on GM-CSF have been implicated in the GM-CSF-GM-CSFR alpha/beta c ternary complex. In studies summarized here, synthetic peptide analogs of GM-CSF sequences were designed and used to map neutralizing epitopes. One neutralizing epitope corresponded to the A helix of GM-CSF, and a synthetic analog displayed biological activity as a GM-CSF antagonist in vitro, suggesting interaction with the GM-CSFR alpha/beta c complex. A second peptide comprising the B and C helices was recognized by monoclonal neutralizing antibodies and similarly displayed antagonist activity. Recombinant antibody (rAb) technology was also employed. An expression library of rAbs from mice immunized with neutralizing anti-GM-CSF antibodies was developed and screened with a neutralizing anti-GM-CSF monoclonal antibody. One clone which displayed receptor binding activity exhibited structural similarity with epitopes on GM-CSF previously implicated as interaction sites with the neutralizing monoclonal antibody. A synthetic peptide analog of the rAb inhibited GM-CSF bioactivity. Critical contact residues were predicted on the basis of structural similarity of the rAb peptide and GM-CSF. These studies indicate the feasibility of using rAbs in bioactive peptide design, providing lead compounds and information regarding contact residues for drug design.