Secondary Metabolites from Cyanobacteria: Complex Structures and Powerful Bioactivities

This review presents natural products from cyanobacteria. Several classes of secondary metabolites are highlighted. Toxic metabolites from these prokaryotic photosynthetic organisms include compounds such as microcystin, anatoxin and saxitoxin, which display hepatotoxicity and neurotoxicity. Their potential as drugs in cancer therapy is discussed based on the cryptophycin class of potent cytotoxic agents. The next part of this review highlights iron chelators from cyanobacteria, including schizokinen, synechobactin and anachelin. The biogenesis of anachelin is investigated as its mechanism of iron acquisition. Several indole alkaloids are then reviewed, from simple carbolines such as bauerines and nostocarboline to complex polycyclic structures such as hapalindole, welwitindolinone and ambiguine. The latter compounds present fascinating structure combined with powerful bioactivities and interesting biogenetic pathways. In the last part, protease inhibitors from cyanobacteria are discussed (cyanopeptolins, micropeptin and oscillapeptin) and their structure/activity relationships and selectivity for trypsin / chymotrypsin are presented. All these examples highlight the large structural variety of cyanobacterial metabolites combined with powerful biological activities. Cyanobacteria can thus be considered a prime source both for novel bioactive compounds and for leads for drugs

Coupling of Dye Analysis and Compound Specific Radiocarbon (14C) Analysis (CSRA) in Heritage Sciences

Natural organic dyes and pigments have been used for millennia to bring colour into our daily lives. Being sourced from a variety of natural sources, they form an extremely varied and large class of compounds, all of which retain the atmospheric 14CO2 of their year of growth. As such these compounds represent ideal candidates for radiocarbon (14C) dating, allowing the identification of or providing information towards the period in which the coloured artefact was created. However, up to now no such analysis has ever been conducted solely on organic colourants within an object. The complex nature of the samples and the sample size limitations with respect to precious and rare art artefacts requires innovative inter- and multidisciplinary approaches. Here we discuss preliminary results in the development of a compound-specific radiocarbon analysis (CSRA) methodology for the analysis of anthraquinone derived red dyes extracted from dyed wool yarns. The aim of this research project is to introduce new routes to date cultural heritage objects, in particular to overcome their intrinsic complexity through the development of CSRA strategies

Classical simulation of entanglement swapping with bounded communication

Entanglement appears under two different forms in quantum theory, namely as a property of states of joint systems and as a property of measurement eigenstates in joint measurements. By combining these two aspects of entanglement, it is possible to generate nonlocality between particles that never interacted, using the protocol of entanglement swapping. We show that even in the more constraining bilocal scenario where distant sources of particles are assumed to be independent, i.e. to share no prior randomness, this process can be simulated classically with bounded communication, using only 9 bits in total. Our result thus provides an upper bound on the nonlocality of the process of entanglement swapping.Comment: 6 pages, 1 figur

The local content of all pure two-qubit states

The (non-)local content in the sense of Elitzur, Popescu, and Rohrlich (EPR2) [Phys. Lett. A 162, 25 (1992)] is a natural measure for the (non-)locality of quantum states. Its computation is in general difficult, even in low dimensions, and is one of the few open questions about pure two-qubit states. We present a complete solution to this long-lasting problem.Comment: 9 pages, 3 figure

Directed Biosynthesis of Phytotoxic Alkaloids in the Cyanobacterium Nostoc 78-12A

Nostocarboline, a chlorinated and N-methylated carbolinium alkaloid, displays potent and selective inhibition of photoautotrophic organisms as well as the malaria parasite Plasmodium falciparum, while showing very low toxicity to bacterial and fungal pathogens, rat myoblasts and crustaceans. New derivatives of nostocarboline incorporating Br, F or methyl substituents have been obtained through precursor-directed biosynthesis in Nostoc 78-12A (identical to Nostoc sp. ATCC 43238) by feeding this cyanobacterium with differently substituted tryptophan derivatives or 6-Br-norharmane (eudistomin N). These experiments substantiate the biosynthetic hypothesis and validate the inherent flexibility of the corresponding enzymes for metabolic engineering. The new derivatives inhibit the growth of the toxic-bloom-forming cyanobacterium Microcystis aeruginosa PCC 7806 above 1 μM. The mode of action of nostocarboline was investigated by using chlorophyll-a fluorescence imaging, and it was demonstrated that a decrease in photosynthesis precedes cell death, thus establishing the phytotoxic properties of this alkaloid

Biologically active secondary metabolites from cyanobacteria

For millennia, nature was the only source of medicine for mankind. Even today natural products represent a large proportion of the drugs in use. In some areas, like cancer or infectious diseases, about 50 % of the compounds used are of natural origin. Cyanobacteria, also known as blue green algae are prokaryotic photoautotrophs. They have been on earth for ~3.5 billion years and were able to adapt to almost every conceivable environment. They have evolved to produce a large diversity of secondary metabolites including alkaloids, terpenes, polyketides and peptides. These compounds display a large array of biological activities and are therefore an interesting source for new drugs or biological tools. However they can also represent a threat to humans because of their potent toxic activities. In this thesis we report the isolation, characterization and the biological evaluation of different cyanobacterial secondary metabolites. The first compounds are the heterocyclic ribosomal peptides aerucyclamides A-D isolated from Microcystis aeruguinosa PCC 7806. Their structure was established by NMR spectroscopy and chemical transformation and degradation. We also proposed a structure revision for the microcyclamide 7806A isolated from the same strain. Antiplasmodial evaluation established submicromolar IC50 values for aerucyclamide B against Plasmodium falciparum; low micromolar values for aerucyclamide C were found against Trypanosoma brucei rhodesiense. The compounds were selective for the parasites over a cell line of L6 rat myoblasts and are thus being considered for further study as antimalarial agents. The ecological role of these compounds was also investigated, aerucyclamides A-C were found to be toxic to the freshwater crustacean Thamnocephalus platyurus, exhibiting LC50 values in the range of 30 µM. The second compound, cyanopeptolin 1020 is an aminohydroxypiperidone (Ahp)-containing depsipeptide, which was isolated from Microcystis aeruguinosa UV-006. Its structure was established by NMR and chemical degradation. This compound is a very potent picomolar trypsin inhibitior (IC50 = 670 pM) and also an inhibitor of human kallikrein (4.5 nM) and factor XIa (3.9 nM). Cyanopeptolin 1020 was found to be toxic against the freshwater crustacean Thamnocephalus platyrus (LC50 = 8.8 µM), which is in the same range as some of the well-known microcystins. These data support the hypothesis that cyanopeptolins can be considered as a second class of toxins in Microcystis and may suggest a re-evaluation of drinking water guidelines solely focussing on microcystins at present. In the third part we describe the new microcystin variants [D-Asp3,(E)-Dhb7]-MC-HtyY, [D-Asp3,(E)-Dhb7]-MC-HtyHty isolated from from Planktothrix rubescens strain No80 and MC-RY, [MeAsp3]-MC-RY and [NMeSer7]-MC-YR isolated from a fresh water lake in Uganda. NMR spectroscopy or MS/MS experiments were used to characterize the structure of these potent protein phosphatase inhibitors. The next chapter describes the biosynthesis of nostocarboline, a chlorinated and N-methylated carbolinium alkaloid produced by Nostoc 78-12A. This compound displays potent and selective inhibition of photoautotrophic organisms. New derivatives of nostocarboline incorporating Br, F or methyl substituents have been obtained through precursor-directed biosynthesis. The mode of action of nostocarboline was investigated using chlorophyll-a fluorescence imaging of and it was demonstrated that a decrease in photosynthesis precedes cell death, thus establishing the phytotoxic properties of this alkaloid. In chapters 6 and 7 we describe the evaluation of 27 crude cyanobacterial extracts for anticancer and antiplasmodial activities respectively. For anticancer activity we used the Telospot method to find inhibitors of telomerase, an attractive target for new chemotherapeutic agents. All the extracts displayed telomerase inhibitor activity. By bioassay guided fractionation we were able to identify four sulfoquinovosyl diacylglycerols from Microcystis aeruguinosa PCC 7806 that inhibit telomerase in the micromolar range (IC50 16 µM). For antiplasmodial activity, extracts of Scytonema cf. crustaceum EAWAG 179a, Tolypothrix distorata var. symplocoides EAWAG 224a, Phormidium foveolarum EAWAG 132, Scytonema sp. CCALA 177 and Anabaena flos-aquae EAWAG 116 displayed promising activity against Plasmodium falciparum. In the last chapter we used the cyanobacterium Lyngbya sp. as a model organism for the evaluation of modified surfaces for inhibition of aquatic biofouling. We demonstrated that a PLL-g-(DHPAA; PEG) copolymer layer on a titanium oxide-coated microscopy glass slide successfully prevent attachment of this aquatic phototroph in culture for up to 100 days

Compound specific radiocarbon ( 14 C) dating of our colorful past ::from theory to practice

For generations, humanity has preserved customs, places, objects, artistic expressions, and values – our cultural heritage. The use of color on cultural heritage objects is ubiquitous and found on artefacts from prehistoric rock art to present day contemporary artworks. The chemical identification of the colored materials used within an artwork often provides information about the work's origin. At the simplest level, a comparison of the materials present with information on their first date of discovery indicates the earliest possible period in which the colored artefact was created. More precise constraints on the date of creation can be provided by radiocarbon (14C) dating, however until today no such analysis has ever been conducted on the compounds responsible for the object's color. The analysis of natural organic dyes and pigments is challenging, as the limited sampling access, their low concentrations and presence in highly complex matrix, are all major challenges to be overcome. The separation of intermingled carbon sources is without question the most difficult problem, yet feasible with the help of compound specific radiocarbon analysis (CSRA). Here, we discuss the potential of radiocarbon dating isolated natural organic dyes and pigments and explore new routes to date cultural heritage objects

Coupling of Dye Analysis and Compound Specific Radiocarbon (14C) Analysis (CSRA) in Heritage Sciences

Natural organic dyes and pigments have been used formillennia to bring colour into our daily lives. Being sourced froma variety of natural sources, they form an extremely varied andlarge class of compounds, all of whichretain the atmospheric14CO2of their year of growth. As such these compoundsrepresent ideal candidates for radiocarbon (14C) dating, allowingthe identification of or providing information towards theperiod in which the coloured artefact was created. However,up to now no such analysis has ever been conducted solelyon organic colourants within an object. The complex natureof the samples and the sample size limitations withrespect toprecious and rare art artefactsrequires innovative inter- andmultidisciplinary approaches. Here we discuss preliminaryresults in the development of a compound-specific radiocarbonanalysis (CSRA) methodology for the analysis of anthraquinonederivedred dyes extracted from dyed wool yarns. The aimof thisresearch project is to introduce newroutes to datecultural heritage objects, in particular to overcome their intrinsiccomplexity through the development of CSRA strategies.ISSN:0009-429

Aerucyclamides A and B: Isolation and Synthesis of Toxic Ribosomal Heterocyclic Peptides from the Cyanobacterium Microcystis aeruginosa PCC 7806

Two new modified hexacyclopeptides, aerucyclamides A and B, were isolated from the toxic freshwater cyanobacterium Microcystis aeruginosa PCC 7806. The constitution was assigned by spectroscopic methods, and the configuration determined by chemical degradation and analysis by Marfey’s method combined with chemical synthesis. Synthetic aerucyclamide B was obtained through oxidation of aerucyclamide A (MnO2, benzene). The aerucyclamides were found to be toxic to the freshwater crustacean Thamnocephalus platyurus, exhibiting LC50 values for congeners A and B of 30.5 and 33.8 μM, respectively