The Benefits of Collaboration.

We have been very humbled by the decision of the Marine Drugs Editors to honor us with a Special Issue dedicated to our efforts over the past 50 years, as well as their invitation to write a guest editorial for this issue [...].

Fifty years of capacity building in the search for new marine natural products.

The Convention on Biological Diversity, and the Nagoya Protocol in particular, provide a framework for the fair and equitable sharing of benefits arising from the utilization of biological resources and traditional knowledge, and ultimately aim to promote capacity-building in the developing world. However, measuring capacity-building is a challenging task due to its intangible nature. By compiling and analyzing a database of scientific peer-reviewed publications over a period of 50 y (1965 to 2015), we investigated capacity-building in global marine natural product discovery. We used publication and authorship metrics to assess how the capacity to become scientifically proficient, prolific, and independent has changed in bioprospecting countries. Our results show that marine bioprospecting is a dynamically growing field of research with continuously increasing numbers of participating countries, publications, and scientists. Yet despite longstanding efforts to promote equitability and scientific independence, not all countries have similarly increased their capacity to explore marine biodiversity within their national jurisdiction areas. Although developing countries show an increasing trend in the number of publications, a few developed countries still account for almost one-half of all publications in the field. Multiple lines of evidence suggest that economic capacity affects how well countries with species-rich marine ecosystems can scientifically explore those resources. Overall, the capacity-building data analyzed here provides a timely contribution to the ongoing international debate about access to and benefit-sharing of biological resources for countries exploring biodiversity within and outside their national jurisdiction areas.

Marine natural products.

Covering: 2015. Previous review: Nat. Prod. Rep., 2016, 33, 382-431This review covers the literature published in 2015 for marine natural products (MNPs), with 1220 citations (792 for the period January to December 2015) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1340 in 429 papers for 2015), together with the relevant biological activities, source organisms and country of origin. Reviews, biosynthetic studies, first syntheses, and syntheses that lead to the revision of structures or stereochemistries, have been included.

Natural products discovery needs improved taxonomic and geographic information.

Covering: up to 2016Marine and terrestrial organisms yield a remarkable chemical diversity and are important sources for discovery of new chemical products. In order to maximize the bioprospecting efficiency of natural products (NP), taxonomy, geography and biodiversity are starting to be used to draw conclusions on which taxonomic groups and/or regions may be of interest for future research. However, accurate taxonomic information and sampling location of source organisms have often been overlooked. Although these issues were already reported a few decades ago and improvements have been made, such outstanding problems are still recurrent in recent peer-reviewed literature. Here, we focus on the importance of taxonomic and geographic identification of source material and illustrate how taxonomic and geographic data of source organisms continues to be poorly handled. It is our opinion that this issue needs to be discussed within the NP community with the ultimate goal of improving publication standards and guaranteeing the scientific principle of research reproducibility. Moreover, by doing so, it will be possible to take advantage of information available in the literature to develop cross-disciplinary meta-analyses that may help to advance the state of the art of NP research and future bioprospecting endeavours.

Marine natural products.

This review covers the literature published in 2014 for marine natural products (MNPs), with 1116 citations (753 for the period January to December 2014) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1378 in 456 papers for 2014), together with the relevant biological activities, source organisms and country of origin. Reviews, biosynthetic studies, first syntheses, and syntheses that lead to the revision of structures or stereochemistries, have been included.

Marine natural products.

This review covers the literature published in 2013 for marine natural products (MNPs), with 982 citations (644 for the period January to December 2013) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1163 for 2013), together with the relevant biological activities, source organisms and country of origin. Reviews, biosynthetic studies, first syntheses, and syntheses that lead to the revision of structures or stereochemistries, have been included.

Marine natural products.

This review covers the literature published in 2012 for marine natural products, with 1035 citations (673 for the period January to December 2012) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1241 for 2012), together with the relevant biological activities, source organisms and country of origin. Biosynthetic studies, first syntheses, and syntheses that lead to the revision of structures or stereochemistries, have been included.

Marine natural products.

This review covers the literature published in 2011 for marine natural products, with 870 citations (558 for the period January to December 2011) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1152 for 2011), together with the relevant biological activities, source organisms and country of origin. Biosynthetic studies, first syntheses, and syntheses that lead to the revision of structures or stereochemistries, have been included.

Biogeography and biodiscovery hotspots of macroalgal marine natural products.

This review covers the literature published for marine natural products isolated from macroalgae and addresses the taxonomic details of source organisms, the chemical types of isolated compounds and the location of sampling sites. The emphasis of this review is on the identification of the most bioprospected taxa and regions, as well as on how these trends have shifted over time.

Marine natural products.

Covering: 2010. Previous review: Nat. Prod. Rep., 2011, 28, 196. This review covers the literature published in 2010 for marine natural products, with 895 citations (590 for the period January to December 2010) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1003 for 2010), together with the relevant biological activities, source organisms and country of origin. Biosynthetic studies, first syntheses, and syntheses that lead to the revision of structures or stereochemistries, have been included.

The isolation of a new S-methyl benzothioate compound from a marine-derived Streptomyces sp.

The application of an HPLC bioactivity profiling/microtiter plate technique in conjunction with microprobe NMR instrumentation and access to the AntiMarin database has led to the isolation of a new 1. In this example, 1 was isolated from a cytotoxic fraction of an extract obtained from marine-derived Streptomyces sp. cultured on Starch Casein Agar (SCA) medium. The 1D and 2D (1)H NMR and ESIMS data obtained from 20 µg of compound 1 fully defined the structure. The known 2 was also isolated and readily dereplicated using this approach.

3,4'-Linked bis(piperidines) related to the haliclonacyclamine class of marine alkaloids: synthesis using crossed-aldol chemistry and preliminary biological evaluations.

Compounds 2-5, incorporating various elements of the 3,4'-bis(piperidine) core associated with the sponge-derived alkaloid haliclonacyclamine A (HA, 1), have been prepared through, inter alia, aldol-type reactions of N-substituted piperidin-4-ones and certain derivatives. Screening of these compounds in various assays, including an ecological one, reveals that compound 5 exhibits allelochemical properties similar to those associated with HA itself.

Cytotoxic and Antifungal Activities of 5-Hydroxyramulosin, a Compound Produced by an Endophytic Fungus Isolated from Cinnamomum mollisimum.

An endophytic fungus isolated from the plant Cinnamomum mollissimum was investigated for the bioactivity of its metabolites. The fungus, similar to a Phoma sp., was cultured in potato dextrose broth for two weeks, followed by extraction with ethyl acetate. The crude extract obtained was fractionated by high-performance liquid chromatography. Both crude extract and fractions were assayed for cytotoxicity against P388 murine leukemic cells and inhibition of bacterial and fungal pathogens. The bioactive extract fraction was purified further and characterized by nuclear magnetic resonance, mass spectral and X-ray crystallography analysis. A polyketide compound, 5-hydroxyramulosin, was identified as the constituent of the bioactive fungal extract fraction. This compound inhibited the fungal pathogen Aspergillus niger (IC(50) 1.56 µg/mL) and was cytotoxic against murine leukemia cells (IC(50) 2.10 µg/mL). 5-Hydroxyramulosin was the major compound produced by the endophytic fungus. This research suggests that fungal endophytes are a good source of bioactive metabolites which have potential applications in medicine.

Interactions of halichondrin B and eribulin with tubulin.

Compounds that modulate microtubule dynamics include highly effective anticancer drugs, leading to continuing efforts to identify new agents and improve the activity of established ones. Here, we demonstrate that [(3)H]-labeled halichondrin B (HB), a complex, sponge-derived natural product, is bound to and dissociated from tubulin rapidly at one binding site per αß-heterodimer, with an apparent K(d) of 0.31 µM. We found no HB-induced aggregation of tubulin by high-performance liquid chromatography, even following column equilibration with HB. Binding of [(3)H]HB was competitively inhibited by a newly approved clinical agent, the truncated HB analogue eribulin (apparent K(i), 0.80 µM) and noncompetitively by dolastatin 10 and vincristine (apparent K(i)'s, 0.35 and 5.4 µM, respectively). Our earlier studies demonstrated that HB inhibits nucleotide exchange on ß-tubulin, and this, together with the results presented here, indicated the HB site is located on ß-tubulin. Using molecular dynamics simulations, we determined complementary conformations of HB and ß-tubulin that delineated in atomic detail binding interactions of HB with only ß-tubulin, with no involvement of the α-subunit in the binding interaction. Moreover, the HB model served as a template for an eribulin binding model that furthered our understanding of the properties of eribulin as a drug. Overall, these results established a mechanistic basis for the antimitotic activity of the halichondrin class of compounds.

Marine natural products.

This review covers the literature published in 2008 for marine natural products, with 829 citations (613 for the period January to December 2008) referring to compounds isolated from marine microorganisms and phytoplankton, green algae, brown algae, red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1065 for 2008), together with the relevant biological activities, source organisms and country of origin. Biosynthetic studies, first syntheses, and syntheses that lead to the revision of structures or stereochemistries, have been included.

Isolation and characterization of diastereomers of discorhabdins H and K and assignment of absolute configuration to discorhabdins D, N, Q, S, T, and U.

Investigations of four different sponge populations of Latrunculia species collected in New Zealand waters has led to the characterization of a new diastereomer of discorhabdin H, named discorhabdin H2, confirmation of the structure of discorhabdin K ((+)-7), and presentation of a new diastereomer, discorhabdin K2 ((-)-8). In each case the structures were established by extensive NMR and MS studies and the absolute configurations interrogated by electronic circular dichroism (ECD). Absolute configurations were assigned to the known metabolites discorhabdins H, D, 2-hydroxy-D, N, and Q by comparison of ECD spectra with those recorded for discorhabdin alkaloids of defined absolute configuration, while the configurations of discorhabdins S, T, and U were assigned by semisynthesis from (+)-(6S,8S)-discorhabdin B.

Explorative solid-phase extraction (E-SPE) for accelerated microbial natural product discovery, dereplication, and purification.

Microbial natural products (NP) cover a high chemical diversity, and in consequence extracts from microorganisms are often complex to analyze and purify. A distribution analysis of calculated pK(a) values from the 34390 records in Antibase2008 revealed that within pH 2-11, 44% of all included compounds had an acidic functionality, 17% a basic functionality, and 9% both. This showed a great potential for using ion-exchange chromatography as an integral part of the separation procedure, orthogonal to the classic reversed-phase strategy. Thus, we investigated the use of an "explorative solid-phase extraction" (E-SPE) protocol using SAX, Oasis MAX, SCX, and LH-20 columns for targeted exploitation of chemical functionalities. E-SPE provides a minimum of fractions (15) for chemical and biological analyses and implicates development into a preparative scale methodology. Overall, this allows fast extract prioritization, easier dereplication, mapping of biological activities, and formulation of a purification strategy.

Pederin-type pathways of uncultivated bacterial symbionts: analysis of o-methyltransferases and generation of a biosynthetic hybrid.

The complex polyketide pederin is a potent antitumor agent isolated from Paederus spp. rove beetles. We have previously isolated a set of genes from a bacterial endosymbiont that are good candidates for pederin biosynthesis. To biochemically study this pathway, we expressed three methyltransferases from the putative pederin pathway and used the partially unmethylated analogue mycalamide A from the marine sponge Mycale hentscheli as test substrate. Analysis by high-resolution MS/MS and NMR revealed that PedO regiospecifically methylates the marine compound to generate the nonnatural hybrid compound 18-O-methylmycalamide A with increased cytotoxicity. To our knowledge, this is the first biochemical evidence that invertebrates can obtain defensive complex polyketides from bacterial symbionts.

Antitumour polyether macrolides: four new halichondrins from the New Zealand deep-water marine sponge Lissodendoryx sp.

The isolation is reported of four new variants of the halichondrin B skeleton, very minor potently bioactive components from the Poecilosclerid sponge Lissodendoryx sp. These compounds were isolated in microgram quantities only from a collection of 1tonne of sponge. The structural elucidations relied heavily on the use of capillary NMR spectroscopy and the application of an HSQC-DEPT overlay technique.

Isolation of 2-pyridone alkaloids from a New Zealand marine-derived penicillium species.

Fermentation of a Penicillium sp. isolated from a surface-sterilized thallus segment of the brown alga Xiphophora gladiata, collected from Macrocarpa Point, Otago, New Zealand, in half-strength potato dextrose broth led to the isolation and characterization of three alkaloids: the known N-hydroxy-2-pyridone, PF1140 (1), and two new 2-pyridones, 2 and 3.