Volume 84, Issue 6

The IUPAC-sponsored joint meeting of the 27th International Symposium on the Chemistry of Natural Products (ISCNP-27) and the 7th International Conference on Biodiversity (ICOB-7) was held in Brisbane, Australia from 10 to 15 July 2011. The meeting was co-chaired by Prof. Ron Quinn from Griffith University and Prof. Mary Garson from the University of Queensland. The meeting brought together a broad cross-section of highly renowned scientists from academia, government, and industry, who presented their findings in 42 plenary and invited talks. An excellent diversity of contributed short talks were provided by a further 20 speakers. Three successful sessions were devoted to short (3 min) oral poster presentations given by 18 early-career scientists describing the research presented in their posters. A total of 76 posters were also presented. Scientists from 24 countries presented their research at the conference. Topics covered at the symposia included: discovery of new metabolites, isolation and structure elucidation, synthesis, neglected diseases, biosynthesis, engineered biosynthesis, chemical ecology, new methodology, and biodiversity. The chemistry from a rich diversity of sources was covered, including marine invertebrates, insects, plants, fungi, bacteria, myxobacteria, cyanobacteria, and even mammalian venoms. The 14 papers included in this issue of Pure and Applied Chemistry are based upon lectures presented at ISCNP-27/ICOB-7. The papers represent a good cross-section of the major themes in natural products research presented during the meeting and demonstrate the multidisciplinary nature and extensive breadth of applications that natural products research can provide to the wider community. The next meeting in this series is scheduled to take place in Shanghai in 2013. Anthony R. Carroll Conference Editor

Toxic substances that occur in nature have various structures and functions. In fact, the very novelty of their structures and functions sometimes extends far beyond the realm of human imagination, and the capabilities of these compounds are still largely untapped despite the major advances of modern science. In this report we focus on the most recent developments in this field, with a particular emphasis on natural venoms, marine sunscreen, and marine huge molecules.

Venomous mammals are rare, and only a few species in the orders Insectivora and Monotremata produce toxic venom. Among them, the duckbill platypus ( Ornithorhynchus anatinus ) is one of the two venomous Australian mammals. The adult male platypus carries a spur on each hind leg, which it uses to inject competitors with poison. However, the structure and function of the poison’s active compounds are still imcompletely characterized. We found that crude platypus venom produced potent Ca 2+ influx in human neuroblastoma IMR-32 cells. Guided by this assay, we identified 11 unique peptides, including peptide H–His–Asp–His–Pro–Asn–Pro–Arg–OH, which coincided with the N-terminal domain residues of Ornithorhynchus venom C-type natriuretic peptide (OvCNP). This heptapeptide induced a significant increase in [Ca 2+ ] i in IMR-32 cells at 75 μM; had relatively specific affinities for glutamate, histamine, and GABA A receptors; and facilitated neurogenic twitching in guinea pig ileum specimens at 30 μM. We also established that its proteinous venom fraction strongly hydrolyzed Pro–Phe–Arg–MCA and cleaved a human low-molecular-weight kininogen (LK), similar to porcine pancreas kallikrein. These results strongly indicated that platypus venom contains tissue kallikrein-like protease(s), and its proteolytic activity might synergistically contribute to toxicity through the specific cleavage of other venom constituents.

The application of the title building blocks, the 6,6-dibromobicyclo[3.1.0]hexanes and the cis -1,2-dihydrocatechols, to the total synthesis of crinine and lycorinine alkaloids is described.

Protein kinase C (PKC) isozymes are promising targets for anticancer therapy. Bryostatin-1 (bryo-1), a unique PKC activator with little tumor-promoting activity, is currently in clinical trials for the treatment of cancer. However, its limited availability from natural sources and its synthetic complexity have hampered studies of its mode of action and structural optimization as a therapeutic agent. The development of synthetically more accessible compounds with bryo-1-like activities is thus needed. Recently, we developed a simple and less lipophilic analogue of tumor-promoting aplysiatoxin (ATX) (aplog-1) as a promising lead for bryo-1-like anticancer drugs. Structure–activity studies suggested that local hydrophobicity around the spiroketal moiety of aplog-1 is a crucial determinant of its antiproliferative activity. The hydrophobic analogue (12,12-dimethyl-aplog-1) displayed more potent antiproliferative activity. Moreover, it showed little tumor-promoting activity and even suppressed the tumor promotion by 12- O -tetradecanoylphorbol 13-acetate (TPA) in vivo and in vitro. Aplog-1 and bryo-1 bound selectively to novel PKC isozymes (δ, η, and θ) while tumor promoters bound to both conventional and novel PKC isozymes. These results suggest that the unique biological activities of aplog-1 and bryo-1 are ascribable in part to the ability to bind to PKCδ, but weak binding to conventional PKC isozymes might also be important.

As part of our search for bioactive compounds from plant biodiversity, 29 withanolides were recently isolated from three members of the Solanaceae: Physalis longifolia , Vassobia breviflora , and Withania somnifera . Six derivatives were prepared from these naturally occurring withanolides. All compounds were evaluated for in vitro antiproliferative activity against an array of cell lines [melanoma cell lines (B16F10, SKMEL28); human head and neck squamous cell carcinomas (HNSCC) cell lines (JMAR, MDA1986, DR081-1); breast cancer cell line (Hs578T), and non-malignant human cell line (MRC5)]. This led to the discovery of 15 withanolides, with IC 50 values in the range of 0.067−17.4 μM, including withaferin A, withaferin A 4,27-diacetate, 27- O -glucopyranosylwithaferin A, withalongolide H, withalongolide C, withalongolide A, withalongolide A 4,27-diacetate, withalongolide A 4,19,27-triacetate, withalongolide B, withalongolide B 4-acetate, withalongolide B 4,19-diacetate, withalongolide D, withalongolide E, withalongolide G, and 2,3-dihydrowithaferin A 3- O -sulfate. In order to update the growing literature on withanolides and their activities, we summarized the distribution, structural types, and antiproliferative activities for all published withanolides to date. The structure–activity relationship analysis (SARA) confirmed the importance of the presence of a ∆ 2 -1-oxo-functionality in ring A, a 5β,6β-epoxy or 5α-chloro-6β-hydroxy grouping in ring B, and nine-carbon side chain with a lactone moiety for cytotoxic activity. Conversely, the SARA indicated that the –OH or –OR groups at C-4, 7, 11, 12, 14, 15, 16, 17, 18, 19, 20, 23, 24, 27, and 28 were not contributors to the observed antiproliferative activity within the systems analyzed.

Chaetocin, a natural product isolated from fungi of Chaetomium species, is a member of the epipolythiodiketopiperazines (ETPs), which have various biological activities, including cytostatic and anticancer activities. Recently, the inhibitory activity toward histone methyltransferases (HMTs) was discovered for chaetocin. We previously reported the first total synthesis of chaetocin and various derivatives. During studies on the structure–activity relationship for HMT inhibition, we found that the enantiomer of chaetocin ( ent -chaetocin) is a more potent apoptosis inducer than natural chaetocin in human leukemia HL-60 cells. Mechanistic studies showed that ent -chaetocin induces apoptosis through the caspase-8/caspase-3 pathway.

Studies toward the synthesis of three biologically active [5,6]-benzannulated spiroketal natural products are described. The first total synthesis of paecilospirone is reported, employing a late-stage, pH-neutral spiroketalization. A formal synthesis of γ-rubromycin is described, where the spiroketal moiety is formed by delicate manipulation of the electronic properties of the spirocyclization precursor. Finally, model work toward the total synthesis of berkelic acid is summarized, introducing a novel Horner–Wadsworth–Emmons/oxa-Michael (HWE/oxa-M) cascade to access the spiroketal precursor.

In this communication, selected results obtained in the course of a 10-year Sino-Italian collaborative project are presented. During this collaboration, several studies on marine organisms collected in the South China Sea have been conducted, resulting in the characterization of a large number of novel natural products. The main interest has been focused on sponges, cnidarians, and molluscs. Here, the recent research, including some not yet published studies, on cnidarians and molluscs, in particular, opisthobranchs and pulmonates, will be briefly described. The study of cnidarians and pulmonates led to isolate molecules, in particular, biscembranoids and polypropionates, displaying carbon skeletons already described in previous papers. Our studies resulted in their complete structural characterization including the absolute stereochemistry that was clarified by coupling X-ray diffraction to circular dichroism (CD) spectra analysis. Some unique nitrogenous molecules containing either an isonitrile function or an 1,2,4-oxadiazole moiety, this latter found for the first time in a marine organism, as well as known sesterterpenoids and diterpenoids were isolated from opisthobranchs. Owing to their anatomical location, these metabolites should play a relevant role in the protection of the molluscs. Finally, a series of alkaloids structurally related to known anticancer agents were also characterized.

A microbial fraction library has been constructed as a part of RIKEN Natural Products Depository (NPDepo) to discover and isolate novel metabolites with unique biological activity from microbial sources efficiently and rapidly. The fraction library was made by a systematic separation method based on basic chromatographic techniques. Each fraction in the library was analyzed by liquid chromatography/mass spectrometry (LC/MS) to reveal physicochemical properties of each metabolite within the fraction, and the results were applied to construct a database for rapid discovery of novel and structurally unique compounds. We developed a new type of metabolite database called MP (microbial products) plot to visualize each metabolite on a 2D area. The combination of the fraction library and the database led to the discovery and isolation of novel metabolites, verticilactam, which was a 16-membered macrolactam with an unprecedented β-keto-amide moiety, and spirotoamides A and B, which had a highly substituted 6,6-spiroaccetal moiety and a carboxamide moiety. Moreover, based on the utilization of the MP plot, the new capacity of a streptomycete to produce specific metabolites was discovered.

Myxobacteria are an excellent source of novel secondary metabolites with a range of biological activities. This review details the synthesis of several examples of these natural products. The total synthesis of all the members of the crocacin family is presented where the stereochemistry of the stereotetrad was set via a tin-mediated syn -aldol reaction followed by selective anti -reduction. The other key step in the route to crocacins A, B, and D was the introduction of the enamide functionality by acylation of an enecarbamate. A formal synthesis of apicularen A is also discussed, which involved a base-induced macrolactonization reaction and a transannular oxy-Michael cyclization to secure the tetrahydropyran ring. Finally, the total synthesis of deshydroxyajudazol B is summarized. This route details a modified approach to the 2,4-disubstituted oxazole, and a Diels–Alder reaction followed by aromatization was utilized to form the isochromanone moiety. A highly efficient Sonogashira coupling followed by partial reduction then gave deshydroxyajudazol B.

The enantioselective synthesis of a naturally occurring pyranonaphthoquinone isolated from a Thai endemic plant, Ventilago harmandiana , has been achieved. L-Rhamnose and gallic acid were used as the starting materials. A new C -1-glycosidation of L-rhamnal with trimethyl aluminum in the presence of a catalytic amount of ytterbium(III) triflate was developed. A new reagent, PhSCF 2 H/SnCl 4 , for the formylation of partially deactivated and hindered aromatic compounds has been introduced. Phenylthiophthalide was used efficiently as a cycloannulating agent in the Hauser cycloannulation reaction, employing slightly excess lithium t -butoxide as a base with a catalytic amount of lithium chloride. The synthetic route developed is applicable for the synthesis of other analogues with substituents at the aromatic and pyran rings.

Saxitoxin (STX), a neurotoxin isolated from Alaskan butter clam, Saxidomus giganteus , inhibits voltage-gated sodium channels by binding to the pore-forming p-loop region. Here we describe stereospecific syntheses of STX and its natural derivatives, (+)-decarbamoylsaxitoxin (dcSTX) and (+)-gonyautoxin3 (GTX3).

Paclitaxel (Taxol ® ) is one of the most important anticancer agents developed over the last 30 years. Its primary mechanism of action is by interaction with the cellular protein tubulin, causing irreversible polymerization to microtubules. A detailed knowledge of this crucial interaction is thus of paramount importance in the design and development of highly potent analogs and also for the potential development of “non-taxane” tubulin polymerization agents. This review briefly describes the discovery and development of taxol, and then describes our work on delineating the tubulin-binding conformation of paclitaxel by a combination of rotational echo double resonance (REDOR) NMR and molecular modeling. The resulting “T-taxol” conformation was validated by the synthesis of conformationally constrained paclitaxel analogs, which had bioactivities up to 20-fold higher than those of paclitaxel. The review concludes with recent work on the development of a gold nanoparticle derivative of paclitaxel. This delivery method has the potential to lower the dosage of paclitaxel needed while maintaining or increasing its effectiveness, thus significantly improving the benefits of this important chemotherapeutic agent.

The major phytochemical constituents of the widely used medicinal herb Chamaelirium luteum (“false unicorn”) are open-chain cholesterol-derived steroidal saponins. These are unusual in lacking the extra ring(s) derived from the steroidal side chain that are characteristic of the more commonly isolated furostanol and spirostanol saponins. The structures of the major steroidal saponins of C. luteum were determined using a combination of multistage mass spectrometry (MS n ), 1D and 2D NMR experiments, and chemical degradation. The flexible nature of the steroidal side chain in these saponins necessitated determination of their absolute stereochemistry via total synthesis and X-ray crystallography.