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Robert J. Capon - One of the best experts on this subject based on the ideXlab platform.

  • Biologically active natural products from Australian Marine organisms
    Bioactive Compounds from Natural Sources Second Edition, 2011
    Co-Authors: Robert J. Capon
    Abstract:

    Before embarking on a discussion of biologically active natural products from Australian Marine organisms, it is useful spending a moment considering the term biologically active, particularly as relates to the interconnecting themes of Marine chemical ecology and drug discovery. The reasons are twofold. First, some may question the premise that the chemical ecology achievements of primitive Marine creatures could inspire the development of new drugs-particularly drugs applicable to human disease. In response, history has successfully and repeatedly traversed the path from terrestrial plants, animals, and microbes, through traditional medicines to modern pharmacology and therapeutics, so it should come as no surprise that we turn to the Marine “road less travelled” in our search for new routes to better drugs. Second, the proposition that biologically active Metabolites have value inevitably implies the corollary view that biologically inactive Metabolites have no (or lesser) value. The danger of judging by these criteria is that all too often the assessment of biologically active versus inactive is based on a limited set of bioassays. Choose the wrong bioassay(s) and an exquisitely potent and selective biologically active Marine Metabolite can be mistakenly categorized and dismissed as inactive. Put another way, simply because we may not currently know or appreciate the biological activity of a particular Marine Metabolite, it does not mean that it is biologically inactive and thereby lacking in drug discovery potential. But why should we give Marine Metabolites the benefit of the doubt? Surely, if they do not register in the “bioassay of the day,” it is reasonable to assume they are inactive, dismiss them, and move on. The answer, a resounding no, goes to the heart of what natural products are, how they came to exist, and how we might make best use of them. Conventional wisdom has Marine natural products providing host organisms with a survival advantage, typically referred to as a chemical defense. The host organisms can themselves be the biosynthetic source of these Metabolites, or they can acquire them from dietary sources and/or symbiotic/associated organisms (bacteria or microalgae). These chemicals can protect the host from infection (antibiotics, antiparasitics), repel or dissuade predators (antifeedants, toxins), inhibit the development and growth of competitors (selective cytotoxins and cell growth inhibitors), or even guard against UV radiation (sunscreens). They may also enhance reproductive outcomes (sperm attractants), or improve the ability to feed by rapidly immobilizing prey (venoms). This ecological significance can on occasion be tested experimentally. For example, a Marine algal Metabolite that elicits a feeding avoidance response when added to the food pellets of aquaria fish might have an ecological role as an antifeedant against herbivorous reef fish. Similarly, a Marine tunicate Metabolite that is antibacterial toward laboratory strains of human pathogenic bacteria might protect the tunicate from opportunistic pathogens present in seawater, while a Marine sponge Metabolite that selectively kills fast growing human cancer cells in tissue culture might inhibit growth and development of the avalanche of larval species that threaten overgrowth of filter feeding organisms such as sponges. That such insights into Marine chemical ecology are achieved by proxy in the laboratory is an inevitable consequence of the challenges associated with replicating complex Marine ecosystems. Although a number of noteworthy exceptions exist, for the large part we remain ignorant of, or at best hypothesize on, the ecological role played by the vast majority of known Marine Metabolites.

  • The Absolute Stereochemistry of Variabilin and Related Sesterterpene Tetronic Acids
    Natural Product Letters, 1994
    Co-Authors: Robert J. Capon, Tim R. Dargaville, Rohan Andrew Davis
    Abstract:

    The absolute stereochemistry of the Marine Metabolite variabilin (1). has been suggested by degradation. The absolute stereochemistry of related Marine Metabolites, ircinin-1 (2), ircinin-2 (3), (8£,13Z,20Z)-strobobilin (4) and (8Z,13£,20Z)-strobobilin (5), have been tentatively established through comparison of their molecular rotations with those for variabilin.

  • 5 epi isospongiaquinone a new sesquiterpene quinone antibiotic from an australian Marine sponge spongia hispida
    Journal of Natural Products, 1992
    Co-Authors: Sylvia Urban, Robert J. Capon
    Abstract:

    An Australian Marine sponge, Spongia hispida, has been found to contain a new sesquiterpene/quinone identified by detailed spectroscopic analysis and chemical derivatization as the antibiotic 5-epi-isospongiaquinone [3]. The complete stereostructure for 3 was determined by detailed spectroscopic analysis and chemical correlation with the known Marine natural product isospongiaquinone [2]. Co-occurring with 3 was an ethylated analogue, 5-epi-homoisospongiaquinone [4], which was speculated to be an artifact of the isolation process. A revised structure 15 for the known Marine Metabolite, smenorthoquinone [13], is also presented.

  • 5-Epi-isospongiaquinone, a new sesquiterpene/quinone antibiotic from an Australian Marine sponge, Spongia hispida.
    Journal of Natural Products, 1992
    Co-Authors: Sylvia Urban, Robert J. Capon
    Abstract:

    An Australian Marine sponge, Spongia hispida, has been found to contain a new sesquiterpene/quinone identified by detailed spectroscopic analysis and chemical derivatization as the antibiotic 5-epi-isospongiaquinone [3]. The complete stereostructure for 3 was determined by detailed spectroscopic analysis and chemical correlation with the known Marine natural product isospongiaquinone [2]. Co-occurring with 3 was an ethylated analogue, 5-epi-homoisospongiaquinone [4], which was speculated to be an artifact of the isolation process. A revised structure 15 for the known Marine Metabolite, smenorthoquinone [13], is also presented.

Jean-yves Wach - One of the best experts on this subject based on the ideXlab platform.

  • Synthetic Studies on the Sporolides: Exploration of the Enediyne Route
    Synthesis, 2009
    Co-Authors: Karl Gademann, Simone Bonazzi, Massimo Binaghi, Cindy Fellay, Jean-yves Wach
    Abstract:

    Synthetic studies towards the construction of the cyclopenta[a]indene fragment of the heptacyclic Marine Metabolite sporolide are reported based on a hypothetical biosynthesis. The key step of this biogenetic proposal includes a Bergman cyclization of an enediyne precursor. The enediyne target of this synthetic study was prepared by Sonogashira cross-coupling of two fragments, of which the cyclopentane fragment was prepared from cyclopentenone, Morita-Baylis-Hillman reaction, and enantioselective Sharpless dihydroxylation

  • Enantioselective Synthesis of the Sporolide Quinone Acid Fragment
    Synlett, 2009
    Co-Authors: Jean-yves Wach, Karl Gademann
    Abstract:

    The sporolide quinone acid is a key fragment in the biosynthesis of the complex heptacyclic Marine Metabolite sporolide. We report a concise enantioselective route to this fragment, which is obtained in seven steps with 65% overall yield from trimethoxybenzene. The enantioselective transfer reduction is achieved by Ipc2BCl, and the absolute configuration of the product secured by X-ray analysis of its cinchonine salt. The target fragment is then obtained by methylation and oxidation to the quinone by AgO.

Miguel Paya - One of the best experts on this subject based on the ideXlab platform.

  • Inhibition of the NF-κB signaling pathway mediates the anti-inflammatory effects of petrosaspongiolide M
    Biochemical pharmacology, 2003
    Co-Authors: Inmaculada Posadas, Antonio Randazzo, Miguel Paya, María Carmen Terencio, Luigi Gomez-paloma, Maria Jose Alcaraz
    Abstract:

    Abstract Petrosaspongiolide M (PT) is a potent secretory phospholipase A 2 inhibitor and anti-inflammatory agent. This Marine Metabolite reduced the production of nitrite, prostaglandin E 2 , and tumor necrosis factor-α in the mouse air pouch injected with zymosan. These effects were also observed in mouse peritoneal macrophages stimulated with zymosan. Inhibition of these inflammatory mediators was related to reductions in inducible nitric oxide synthase, cyclo-oxygenase-2, and tumor necrosis factor-α expression. Since nuclear factor-κB (NF-κB) appears to play a central role in the transcriptional regulation of these proteins by macrophages, we investigated the effects of PT on this transcription factor. We found that PT was a potent inhibitor of the NF-κB pathway since at 1 μM it strongly decreased NF-κB–DNA binding in response to zymosan, in mouse peritoneal macrophages. Our study also indicated that PT could interfere with a key step in NF-κB activation, the phosphorylation of IκBα, resulting in inhibition of IκBα degradation. The control of a wide range of mediators by PT suggests a potentially wide therapeutic spectrum for this Marine Metabolite in inflammatory conditions.

  • effects of petrosaspongiolide m a novel phospholipase a2 inhibitor on acute and chronic inflammation
    Journal of Pharmacology and Experimental Therapeutics, 1999
    Co-Authors: Providencia Garciapastor, Antonio Randazzo, Luigi Gomezpaloma, Maria Jose Alcaraz, Miguel Paya
    Abstract:

    The Marine product petrosaspongiolide M is a novel inhibitor of phospholipase A2 (PLA2), showing selectivity for secretory PLA2 versus cytosolic PLA2, with a potency on the human synovial enzyme (group II) similar to that of manoalide. This compound was more potent than manoalide on bee venom PLA2 (group III) and had no effect on group I enzymes ( Naja naja and porcine pancreatic PLA2). Inhibition of PLA2 was also observed in vivo in the zymosan-injected rat air pouch, on the secretory enzyme accumulated in the pouch exudate. Petrosaspongiolide M decreased carrageenan paw edema in mice after the oral administration of 5, 10, or 20 mg/kg. This Marine Metabolite (0.01–1.0 μmol/pouch) induced a dose-dependent reduction in the levels of prostaglandin (PG)E2, leukotriene B4, and tumor necrosis factor-α in the mouse air pouch injected with zymosan 4 h after the stimulus. It also had a weaker effect on cell migration. The inflammatory response of adjuvant arthritis was reduced by petrosaspongiolide M, which also inhibited leukotriene B4 levels in serum and PGE2 levels in paw homogenates. In contrast with indomethacin, this Marine compound did not reduce PGE2levels in stomach homogenates. Petrosaspongiolide M is a new inhibitor of secretory PLA2 in vitro and in vivo, with anti-inflammatory properties in acute and chronic inflammation.

  • modulation of acute and chronic inflammatory processes by cacospongionolide b a novel inhibitor of human synovial phospholipase a2
    British Journal of Pharmacology, 1999
    Co-Authors: Pablo Garcia Pastor, Miguel Paya, Salvatore De Rosa, Alfonso De Giulio, Jose M Alcaraz
    Abstract:

    Cacospongionolide B is a novel Marine Metabolite isolated from the sponge Fasciospongia cavernosa. In in vitro studies, this compound inhibited phospholipase A2 (PLA2), showing selectivity for secretory PLA2 (sPLA2) versus cytosolic PLA2 (cPLA2), and its potency on the human synovial enzyme (group II) was similar to that of manoalide. This activity was confirmed in vivo in the 8 h zymosan-injected rat air pouch, on the secretory enzyme accumulating in the pouch exudate. Cacospongionolide B, that is bioavailable when is given orally, reduced the elevated levels of sPLA2 present in paw homogenates of rats with adjuvant arthritis. This Marine Metabolite showed topical anti-inflammatory activity on the mouse ear oedema induced by 12-O-tetradecanoylphorbol acetate (TPA) and decreased carrageenin paw oedema in mice after oral administration of 5, 10 or 20 mg kg−1. In the mouse air pouch injected with zymosan, cacospongionolide B administered into the pouch, induced a dose-dependent reduction in the levels of eicosanoids and tumour necrosis factor α (TNFα) in the exudates 4 h after the stimulus. It also had a weak effect on cell migration. The inflammatory response of adjuvant arthritis was reduced by cacospongionolide B, which did not significantly affect eicosanoid levels in serum, paw or stomach homogenates and did not induce toxic effects. Cacospongionolide B is a new inhibitor of sPLA2 in vitro and in vivo, with anti-inflammatory properties in acute and chronic inflammation. This Marine Metabolite was active after oral administration and able to modify TNFα levels, and may offer an interesting approach in the search for new anti-inflammatory agents. Keywords: Inflammation, phospholipase A2, rat and mouse air pouch, adjuvant arthritis, manoalide, cacospongionolide B Introduction The activation of different phospholipases is a critical step in the biosynthesis of lipid mediators. Phospholipase A2 (PLA2) is a class of enzymes that hydrolyze the acyl group from the sn-2 position of glycerophospholipids, yielding free fatty acids and lysophospholipids. These products or their Metabolites are bioactive lipids modulating different cellular processes. Mammalian cells contain diverse PLA2 which may play a distinct role in cell activation and signal transduction. Moreover, in pathologic states, increased PLA2 activity causes alteration of membrane structure and function as well as an excessive production of lipid mediators and toxic species that contributes to tissue injury. Secretory PLA2 (sPLA2, groups I, II, III and V), cytosolic PLA2 (cPLA2, group IV) and calcium-independent PLA2 have been studied (for review see Serhan et al. (1996); Dennis (1997)). Calcium-independent PLA2 is present in the myocardium and other tissues. This enzyme may regulate the incorporation of arachidonic acid into membrane phospholipids in P388D1 macrophages (Balsinde et al., 1995) and could participate in arachidonic acid release and cell spreading in murine peritoneal macrophages (Teslenko et al., 1997). It has been reported that cPLA2 play an important role in arachidonic acid release in a number of cell systems, e.g. human platelets stimulated with thrombin (Bartoli et al., 1994) or calcium ionophore (Riendeau et al., 1994), permeabilized human neutrophils (Bauldry & Wooten, 1996) or mouse peritoneal macrophages challenged with zymosan or 12-O-tetradecanoylphorbol acetate (TPA) (Qiu & Leslie, 1994). Inflammatory cytokines have been shown to induce cPLA2, resulting in high levels of eicosanoids in airway epithelial cells (Wu et al., 1997), rheumatoid synovial fibroblasts (Hulkower et al., 1994) or mouse osteoblasts (Chen et al., 1997). Group II sPLA2 can act as a signalling agent that mediates cell growth induced by interleukin-1β (IL-1β) (Wada et al., 1997). In addition, it has a role in cell activation and contributes to the inflammatory response. sPLA2 activation may participate in signal transduction events such as CD11b/CD18 (MAC-1) expression on the surface of activated human neutrophils, and adhesion or degranulation (Takasaki et al., 1996; Jacobson & Schrier, 1993). This enzyme activity secreted at inflammatory sites becomes associated with cell surfaces and hydrolyzes phospholipids, thus releasing arachidonic acid, which enters the cell and participate in the increased generation of inflammatory lipid mediators (Pfeilschifter et al., 1993; Miyake et al., 1994). In fact, administration of different types of sPLA2 can induce or amplify inflammatory responses in animals (Vishwanath et al., 1988; Tanaka et al., 1995; Cirino et al., 1994). Interestingly, inflammatory cytokines increase group II PLA2 synthesis and secretion by rheumatoid synovial fibroblasts and other cell types (Pfeilschifter et al., 1993; Bomalaski & Clark, 1993). Thus, IL-1β induces an increase in group II sPLA2 gene expression, but does not increase cPLA2 gene expression or activity, and it provokes a parallel increase in prostaglandin E2 (PGE2) production by rabbit articular chondrocytes (Jacques et al., 1997). Group II sPLA2 has been reported to release arachidonic acid in some systems and may provide the substrate for both cyclo-oxygenase (COX) and 5-lipoxygenase (5-LO) product formation in mouse bone marrow-derived mast cells (Fonteh et al., 1994). In contrast, PLA2 secreted by guinea-pig peritoneal macrophages does not participate in the synthesis of PGE2 accumulating in the media (Marshall et al., 1994). On the other hand, exocytosis of sPLA2 could modulate the activity of cPLA2 by initiating the formation of leukotriene B4 (LTB4), which after release stimulates its own receptor, thus leading to activation of cPLA2 in neutrophils (Wijkander et al., 1995). Exogenously added group I PLA2 is also believed to be involved in arachidonic acid release (Hara et al., 1991), in some cases accompanied by induction of group II PLA2, and recently a group V sPLA2 has been reported to participate in immediate prostanoid generation in the mouse macrophage cell line P388D1 (Balboa et al., 1996). Arachidonic acid mobilization can be dependent on both types of PLA2 in some systems, as in the case of delayed PGD2 generation by COX-2 in rat peritoneal macrophages stimulated by lipopolysaccharide (LPS) (Naraba et al., 1998), as well as in receptor-stimulated P388D1 macrophages (Balsinde & Dennis, 1996), and human umbilical vein endothelial cells (Murakami et al., 1993). In human monocytes stimulated by ionophore or zymosan, cPLA2 would participate preferentially in the release of arachidonic acid for prostaglandin (PG) synthesis, whereas sPLA2 probably releases the substrate for LT synthesis (Marshall et al., 1997). Marine organisms are a rich source of molecules exhibiting PLA2 inhibitory properties in vitro, mainly on secretory enzymes (for review, see Potts et al., 1992). Some of these compounds have been found to reduce experimental inflammatory responses, preferentially after topical application. We have examined the PLA2 inhibitory activity of cacospongionolide B (Figure 1), a new Marine Metabolite isolated from the Mediterranean sponge Fasciospongia cavernosa. The results of our studies demonstrate that cacospongionolide B is a potent inhibitor of sPLA2. We have also assessed its effects on models of acute and chronic inflammation. Figure 1 Chemical structure of cacospongionolide B. Methods sPLA2 assay sPLA2 was assayed by using a modification of the method of Franson et al. (1974). E. coli strain CECT 101 were seeded in medium containing 1% tryptone, 0.5% NaCl and 0.6% sodium dihydrogen orthophosphate, pH 5.0, and grown for 6–8 h at 37°C in the presence of 5 μCi ml−1 [3H]-oleic acid (sp. act. 10 Ci mmol−1). After centrifugation at 2500×g for 10 min, the cells were washed in buffer (0.7 M Tris-HCl, 10 mM CaCl2, 0.1% bovine serum albumin, BSA, pH 8.0), resuspended in saline and autoclaved for 30–45 min. At least 95% of the radioactivity was incorporated into phospholipids. Naja naja venom, porcine pancreatic, bee venom and human recombinant synovial enzymes were diluted in 10 μl of 100 mM Tris-HCl, 1 mM CaCl2 buffer, pH 7.5. Supernatants (10 μl) of exudates from zymosan-injected rat air pouch (Paya et al., 1996) were also used as a source of sPLA2. Enzymes were preincubated at 37°C for 5 min with 2.5 μl of test compound solution or its vehicle in a final volume of 250 μl. Incubation proceeded for 15 min in the presence of 10 μl of autoclaved oleate-labelled membranes and was terminated by addition of 100 μl ice-cold solution of 0.25% BSA in saline to a final concentration of 0.07% w/v. After centrifugation at 2500×g for 10 min at 4°C, the radioactivity in the supernatants was determined by liquid scintillation counting.

Gerald Pattenden - One of the best experts on this subject based on the ideXlab platform.

Yoshikazu Uto - One of the best experts on this subject based on the ideXlab platform.

  • Total synthesis and revision of stereochemistry of the Marine Metabolite trunkamide A.
    The Journal of organic chemistry, 2000
    Co-Authors: Peter Wipf, Yoshikazu Uto
    Abstract:

    The isolation of the cytotoxic Lissoclinum sp. Metabolite trunkamide A was reported in 1996. After completion of a total synthesis in 1999, it became clear that the structure of this Marine natural product had to be revised. We now report the first preparation of actual trunkamide A in a total synthesis that serves as an unambiguous structural and stereochemical proof. Highlights of our synthetic strategy are a Lewis acid assisted aziridine opening that was used for the preparation of the novel reverse-prenylated serine and threonine side chains as well as an efficient oxazoline-thiazoline interconversion on the macrocyclic skeleton. In addition, several stereoisomers prepared by complementary synthetic protocols serve to illustrate the general scope of our methodology and confirm the configurational assignment.

  • Total synthesis of the putative structure of the Marine Metabolite trunkamide A
    Tetrahedron Letters, 1999
    Co-Authors: Peter Wipf, Yoshikazu Uto
    Abstract:

    Abstract The structure assigned to trunkamide A, a cycloheptapeptide alkaloid isolated from the colonial ascidian Lissoclinum sp., was prepared via segment condensations and an efficient oxazoline-thiazoline interconversion. The novel reverse prenylated serine and threonine amino acid building blocks were obtained by Lewis acid assisted opening of aziridines. In light of this total synthesis, the structure of natural trunkamide A needs to be revised.