Volume 81, Issue 6

The IUPAC International Conference on Biodiversity and Natural Products (ICOB-6 & ISCNP-26) was held in Charlottetown, Canada, 13-18 July 2008. This conference represents an amalgamation of the International Conference on Biodiversity (ICOB) and the International Symposium on the Chemistry of Natural Products (ISCNP). Twenty outstanding scientists from academia, government, and industry gave plenary and invited talks, and another 38 short talks were presented by an equally diverse group. Speakers represented 20 different countries and, with poster presenters, a total of 28 countries were represented. Symposia topics included: isolation and structure elucidation, biosynthesis, spectroscopy, synthesis, engineered biosynthesis, natural products as anticancer leads, new methods in natural products, chemical ecology, metabolomics, and genomics. One highlight was the Royal Society of Chemistry’s “Natural Product Reports” lecture award by Jason Micklefield (University of Manchester) on the biosynthetic engineering of nonribosomal lipopeptides. Mary Garson presented an overview of the next IUPAC meeting in this series to be held in 2011 in Brisbane, Australia. This issue of Pure and Applied Chemistry comprises a collection of 12 papers based on lectures delivered at ICOB-6/ISCNP-26. These reports feature the major themes of the conference and thus provide a representative view of current activity in the expansive field of biodiversity and natural products. As will be evident from reading this issue, marine organisms continue to serve as a prolific source of bioactive natural products with varied applications. Questions about the ecological role of marine natural products continue to intrigue research groups, and synthetic and biosynthetic studies are being used to develop methods to produce both known natural products and unnatural derivatives. Russell G. Kerr Conference Editor

Dinogunellins A-D, ichthyootoxic phospholipids, have been isolated from the mature eggs of the northern blenny Stichaeus grigorjewi . Their structures were determined based on spectral and chemical methods as a mixture of 2’- or 3’-acylated adenosine 5’-phosphate linked to the α-carboxyl group of L-asparagine through a P-N bond.

Marine macro- and micro-organisms collected in Okinawa are good sources of compounds with intriguing structures and interesting biological activities. Synthetic hybrid molecules of caffeine and eudistomin D from tunicates Eudistoma sp. were found to show better potency as adenosine receptor ligands than caffeine, and one of them exhibits potent activity for adenosine receptors tested, especially for A 3 subtype. Potent cytotoxic polyene macrolides from a tunicate Cystodytes sp. were found to be potent osteoclast inhibitors and to inhibit vacuolar type H+-ATPase (V-ATPase) of both mammalian and yeast cells. Amphidinolactones A and B are new macrolides from a dinoflagellate Amphidinium sp., and a potent cytotoxic macrolide from another strain was found to target actin cytoskeleton. Theonezolide A, a long-chain polyketide from a sponge Theonella sp., induces a drastic shape change in platelets by reorganization of microtubules. The stereochemistry of many chiral centers in theonezolide A was elucidated by spectral data and chemical means. Metachromins L-Q are new sesquiterpenoid quinones with an amino acid residue, while nakijiquinones E and F were the first dimeric sesquiterpenoid quinones possessing a 3-aminobenzoate moiety. Halichonadin E is the first hetero-dimeric sesquiterpenoid with eudesmane and aromadendrane skeletons linked through a urea fragment isolated from a sponge Halichondria sp. Pyrinadine A and nakinadine A are novel bis-pyridine alkaloids from sponges, while nagelamides are new bromopyrrole alkaloids from a sponge Agelas sp. Here, the structures and bioactivities of these interesting marine natural products will be described.

A series of heteronemin-related antitubercular scalaranes, both from natural products and from chemical derivatization, were subjected to structure-activity investigations. Based on the activity profile, three main regions; i.e., the substituted groups hovering over C-19/C-18 and furan moiety, the functionalities in the vicinity of C-16 and the right-hand side of ring D, and the substituted groups on C-12, were speculated as the areas influencing the antitubercular activity of the scalaranes. The results suggested the promising possibility for the further investigation towards the modes of actions and/or target sites of the compounds.

A screening of marine bacteria for antimicrobial activity resulted in the isolation of Bacillus pumilus (SP21) from a sediment sample collected in the Bahamas. A bioassay-guided fractionation led to the isolation of five surfactin analogs, glycocholic acid, amicoumacins A and B in addition to three new compounds named lipoamides A-C. The chemical structure of all the bioactive compounds was elucidated using spectroscopic methods including 2D NMR and MS. The antimicrobial activity of each compound was evaluated against a panel of pathogens and is reported herein.

A very little studied marine sponge Callyspongia sp. collected off the coast of Martinique was chemically investigated. The study led to the isolation and structure characterization of two new 3-alkylpyridinium salts which belonged to the recently isolated pachychaline family. Structures were elucidated by 1D, 2D NMR and detailed high-resolution electron spray ionization mass spectra (HRESIMS)-MS studies. The use of HRESIMS-MS studies proved to be highly efficient to identify two other close derivatives in a mixture. Finally, these studies allowed us to propose a general biosynthetic pathway leading to important 3-alkylpyridinium salts.

Precursor-directed biosynthesis offers opportunities to modify natural products and obtain structurally complex metabolites without the need for chemical synthesis. However, such opportunities are limited owing to the inherent substrate specificity of biosynthetic enzymes. The jadomycins are a family of natural products produced by the soil microbe Streptomyces venezuelae ISP5230. Their biosynthesis contains one step that is potentially non-enzymatic, namely, the condensation of a biosynthetic aldehyde and an amino acid that leads to a uniquely substituted oxazolone ring. Variation of amino acids in the culture media enables the production of a wide array of substituted oxazolones. These analogs have been shown to have a variety of biological activities against cancer cell lines and also against Gram-positive bacteria. Herein, we report the first isolation and characterization of jadomycin L and jadomycin L aglycone from 8 L of bacterial culture for solid tumor efficacy studies.

A collaborative multidisciplinary research project is described in which new natural product anticancer drug leads are obtained from a diverse group of organisms, constituted by tropical plants, aquatic cyanobacteria, and filamentous fungi. Information is provided on how these organisms are collected and processed. The types of bioassays are indicated in which crude extracts of these acquisitions are tested. Progress made in the isolation of lead bioactive secondary metabolites from three tropical plants is discussed.

Biosynthetic engineering involves the reprogramming of genes that are involved in the biosynthesis of natural products to generate new "non-natural" products, which might otherwise not exist in nature. Potentially this approach can be used to provide large numbers of secondary metabolites variants, with altered biological activities, many of which are too complex for effective total synthesis. Recently we have been investigating the biosynthesis of the calcium-dependent antibiotics (CDAs) which are members of the therapeutically relevant class of acidic lipopeptide antibiotics. CDAs are assembled by nonribosomal peptide synthetase (NRPS) enzymes. These large modular assembly-line enzymes process intermediates that are covalently tethered to peptidyl carrier protein (PCP) domain bonds bonds, which makes them particularly amenable to reprogramming. The CDA producer, Streptomyces coelicolor , is also a genetically tractable model organism which makes CDA an ideal template for biosynthetic engineering. To this end we have elucidated many of the key steps in CDA biosynthesis and utilized this information to develop methods that have enabled the engineered biosynthesis of wide range of CDA-type lipopeptides.

In recent years, members of the marine actinomycete genus Salinispora have proven to be a precious source of structurally diverse secondary metabolites, including the potent anticancer agent salinosporamide A and the enediyne-derived sporolides. The tremendous potential of these marine-dwelling microbes for natural products biosynthesis, however, was not fully realized until sequencing of the Salinispora tropica genome revealed the presence of numerous orphan biosynthetic loci besides a plethora of rare metabolic pathways. This contribution summarizes the biochemical exploration of this prolific organism, highlighting studies in which genome-based information was exploited for the discovery of new enzymatic processes and the engineering of unnatural natural products. Inactivation of key genes within the salinosporamide pathway has expanded its inherent metabolic plasticity and enabled access to various salinosporamide derivatives by mutasynthesis. New insights into the biosynthesis of the sporolides allowed us to increase production titers of these structurally complex molecules, thereby providing the means to search for the DNA cleaving presporolide enediyne.

X-ray crystallographic data available from complexes of natural and synthetic molecules with the enzyme thrombin has led to the design and synthesis of truncated and hydrid molecules exhibiting excellent inhibition in vitro. The design element has also been extended to the synthesis and in vitro inhibition of a series of achiral molecules deploying aromatic and heterocyclic core motifs with appropriately functionalized appendages that provide excellent binding interactions at the S 1 , S 2 , and S 3 sites of thrombin. Excellent selectivity for thrombin over trypsin has also been observed. Thus, studies in total synthesis of highly active natural aeruginosins have inspired further work toward truncated and hybrid analogs with excellent inhibitory activities. Structure-based organic synthesis has guided our research from natural products toward unnatural drug-like prototypes.

The discovery of new ecologically active compounds often triggers the development of basic scientific concepts in the field of biological sciences, since such compounds have direct physiological and behavioral effects on other living organisms. We have focused on the identification of natural key compounds that control biologically and physiologically intriguing phenomena. We describe three recent aspects of chemical ecology that we have investigated: natural toxins, coral communities, and symbiotic relationships. Blarina toxin (BLTX) is a lethal mammalian venom that was isolated from the short-tailed shrew. Duck-billed platypus venom shows potent Ca2+ influx in neuroblastoma cells. The venom of the solitary wasp contains arginine kinase-like protein and is used to paralyze its prey to feed its larva. The ecological behaviors of corals are controlled by combinations of small molecules. The polyol compound symbiodinolide may serve as a defense substance for symbiotic dinoflagellates to prevent digestion of their host animals. These compounds reveal the wonder of nature, in both terrestrial and marine ecological systems.

Marine sponges and corals are widely recognized as rich sources of novel bioactive natural products. These organisms are frequently colonized by bacteria. Some of these bacteria can be pathogenic or serve as beneficial symbionts. Therefore, these organisms need to regulate the bacteria they encounter and resist microbial pathogens. One method is by chemical defense. Antimicrobial assays performed with extracts of 23 Red Sea corals and sponges against bacteria isolated from their natural environment revealed considerable variability in antimicrobial activity. Soft corals exhibited appreciable activity; sponges showed variability, and stony corals had little or no activity. Among the soft corals, Xenia macrospiculata exhibited the highest activity. Bioassay-directed fractionation of the extract indicated that the activity was due to a range of compounds, one of which was isolated and identified as the diterpene desoxyhavannahine. Among the sponges, Amphimedon chloros exhibited strong activity. Bioassay-directed fractionation resulted in the isolation of the pyridinium alkaloid antibiotics, the halitoxins and amphitoxins. These compounds showed selective activity against specific bacteria, rather than being broad-spectrum. They were highly active against seawater bacteria, whereas bacteria associated with the sponge were resistant. This selective toxicity may be important in enabling certain bacteria to live in close association with their sponge host while it maintains a chemical defense against microbial pathogenesis. The halitoxin-resistant bacteria were identified by 16S rRNA gene analysis as Alphaproteobacteria , closely related to other Alphaproteobacteria isolated from various marine sponges. The study of microbial communities associated with sponges and corals has important implications for the production of symbiont-derived bioactive compounds and for the use of corals and sponges as source material for microbial diversity in screening programs for natural products.

Amphotericin B (AmB) exerts its pharmacological effects by forming a barrel-stave assembly in fungal membranes. To examine the interaction between AmB and ergosterol or cholesterol, 13C- and 19F-labeled covalent conjugates were prepared and subjected to solid-state NMR measurements. Using rotor-synchronous double resonance experiments such as REDOR and RDX, we estimated the distance between the fluorine atom and its nearest carbon in the heptaene moiety to be less than 8.6 Å, indicating that the B ring of ergosterol comes close to the AmB polyene moiety. Conformational search of the AmB-ergosterol conjugate using the NMR-derived constraints suggested that ergosterol molecules surround the AmB assembly in contrast to the conventional image where ergosterol is inserted into AmB molecules. AmB-AmB bimolecular interaction was examined by using 13C- and 19F-labeld AmBs in dimyritoylphosphatidylcholine membrane without sterols. 13C-19F dipolar interactions deriving from both head-to-head and head-to-tail orientations were observed in the REDOR experiments. The interactions between AmB and acyl chains of the phospholipid were also detected.

This document defines class names of polymers based on the class names of starting monomers and characteristic features of the chemical constitution of polymer molecules (macromolecules), i.e., class names that have gained general acceptance in the polymer and material literature, science and technology as well as in public. The glossary is divided into three parts: Source-based class names, which identify common classes of starting monomers such as "acrylic", "diene", "phenolic", "vinylic". Class names based on chemical structure, which identify characteristic groups in the main chains (backbones) of the polymer molecules such as (i) inter-unit groups derived from functional groups, e.g., "amide", "ester", "ether"; (ii) a specific group of atoms, e.g., "alkenylene", "siloxane", "sulfone"; (iii) ring structures, e.g., "benzimidazole", "benzoxazole", "quinoxaline". Class names based on molecular architecture, which identify mainly the overall shapes of polymer molecules through the type of their graphical representation such as "linear", "branched", "dendritic", "comb". Each part of the glossary is arranged in a non-hierarchical alphabetical order. Each entry provides: (a) the polymer class name; (b) its definition; (c) specific or generic examples including IUPAC names and a structure or graphical representation; (d) relations to other polymer classes and subclasses; (e) notes on the inclusion or exclusion of borderline cases. An alphabetical index of all class names is included.