Phytochemistry Reviews (v.9, #4)

Bioactive natural products from marine sponges and fungal endophytes by Peter Proksch; Annika Putz; Sofia Ortlepp; Julia Kjer; Mirko Bayer (475-489).
This review highlights recent findings of our group on bioactive marine natural products isolated from marine sponges and marine derived fungi. The activated chemical defence of the Mediterranean sponge Aplysina aerophoba is introduced as an example of a dynamic response of marine sponges to wounding. Following tissue disrupture preformed brominated isoxazoline alkaloids are enzymatically cleaved and thereby give rise to aeroplysinin-1 which is believed to protect sponges from invasion of pathogenic bacteria. A preliminary characterization of the membrane bound enzyme(s) involved in the cleavage reaction is presented. Bromotyrosine derived, oxime group bearing peptides, the so called bastadins, obtained from the sponge Ianthella basta and some of their synthetic derivatives were shown to exhibit pronounced antifouling activity against larvae of the barnacle Balanus improvisus. The antifouling activity could be traced to the oxime group as an important pharmacophore that was also found to be present in other sponge derived natural products exhibiting antifouling activity. Marine derived fungi that reside within invertebrates such as sponges or inside Mangrove plants are emerging as a new source of bioactive metabolites as demonstrated for Aspergillus ustus and Alternaria sp. that were isolated from the sponge Suberites domuncula or from the Mangrove plant Sonneratia alba, respectively. The former fungus yielded new moderately cytotoxic sesquiterpenoids of the drimane type whereas the latter was found to produce polyketides such as alternariol that exhibited strong and selective inhibitory activity against several protein kinases, for instance Aurora A and B which are targets for anticancer chemotherapy.
Keywords: Activated defence; Antifouling activity; Chemical ecology; Drug discovery; Protein kinase inhibitors

Palytoxins: A still haunting Hawaiian curse by Patrizia Ciminiello; Carmela Dell’Aversano; Ernesto Fattorusso; Martino Forino (491-500).
Palytoxins are a class of extremely potent non-proteic marine biotoxins, whose main biological target is the Na+/K+-ATPase. Since its isolation in 1971 from samples of Hawaiian Palythoa spp., palytoxin has drawn scientists’ attention from across the world because of its high toxicity, intriguing chemical structural architecture, and involvement in fascinating ancient Hawaiian folklore. Palytoxins have recently spread also to more temperate areas, such as the Mediterranean Sea causing severe human intoxications. Over the past years our scientific work has brought to light the occurrence of new palytoxin analogs by extensive NMR investigation and a new liquid chromatography tandem mass spectrometry method set up following the Mediterranean toxic outbreaks.
Keywords: Palytoxin; Marine biotoxins; Palythoa spp.

Approaches to the total synthesis of biologically active natural products: studies directed towards bryostatins by Anthony P. Green; Simon Hardy; Alan T. L. Lee; Eric J. Thomas (501-513).
Progress on a total synthesis of the marine natural products, the bryostatins, is reviewed. Following studies aimed at the synthesis of the 1,16- and 17,27-fragments, procedures for the assembly of the macrocyclic ring of the bryostatins were investigated. Although ring-closing metathesis was not found to be useful for the synthesis of bryostatins with geminal dimethyl groups at C18, the modified Julia reaction was found to be useful for the stereoselective formation of the 16,17-double-bond and led to a synthesis of an advanced macrocyclic intermediate. Several novel synthetic procedures feature in this work.
Keywords: Total synthesis; Bryostatins; Stereoselectivity; Marine natural products; Alkene synthesis

Marine endoperoxides as antimalarial lead compounds by Ernesto Fattorusso; Orazio Taglialatela-Scafati (515-524).
Malaria, a pathology caused by protozoa belonging to the genus Plasmodium, is one of the major threats to global health, with about 300–500 million new clinical cases occurring every year and 1–3 million annual deaths. The recrudescence in the number of fatal cases registered in recent years can be attributed to the diffusion of multi-drug resistant strains of Plasmodium, which make less effective the limited armamentarium of available drugs. Living organisms are a recognized source of potentially bioactive molecules and, among them, marine natural products are emerging as one of the most interesting sources to be exploited for the discovery of new antimalarial compounds. In this article we will report results obtained for a single class of marine metabolites, namely endoperoxide-containing derivatives. Many of these molecules possess a simple six-membered 1,2-dioxygenated ring bearing two or three alkyl/aryl groups of different complexity. They can be divided according to the group linked at one of the two endoperoxide-oxygen bearing carbons: peroxyketal derivatives (methoxy group) or non-peroxyketal derivatives (methyl/ethyl groups). Molecules belonging to these classes show in vitro antimalarial activity in the nanomolar range on chloroquine-resistant strains. A number of investigations gave insights into the mechanism of action of these molecules, suggesting structural changes to optimize their antimalarial activity.
Keywords: Malaria; Marine organisms; Artemisinin; Peroxides; Peroxyketal

Scientific study of paralytic shellfish poisoning toxins (PSTs) started in the early XXth century. In the 1920s it was understood the link between the toxicity observed in mussels with certain microalgae species. The poison was eventually purified from the clam Saxidomus giganteus, taking its name from it: saxitoxin (STX). Along the 1970s and 1980s it was understood that other STX analogues existed, both in dinoflagellates and bivalves. These were grouped into three major occurring families: the carbamate, N-sulfocarbamoyl and decarbamoyl, depending on the variation of the side chain of the tetrahydropurine core. The deoxydecarbamoyl family was additionally recognised in the dinoflagellate Gymnodinium catenatum. Chemical research into these STX analogues was conducted worldwide during the 1990s mainly by HPLC with pre- or post-column oxidation and fluorescence detection. Implementation of fluorescence detection with spectral capabilities and mass spectrometry detection during the 2000s led to the recognition of new analogues. Metabolites originated by single or double hydroxylation at C11 position were found in mussels, and later suspected in other bivalves. Designated M1-M4, these present very low fluorescence, and can only be studied resorting to HILIC-MS. Three hydroxybenzoate analogues were characterised as an important toxin fraction of the dinoflagellate Gymnodinium catenatum, and named GC1-GC3. Later, many more analogues were suspected: the corresponding N1-hydroxyl variants of GC1-GC3 (GC4-GC6), di-hydroxybenzoate variants (GC1a-GC6a), and sulphate-benzoate variants (GC1b-GC6b). In bivalves, carbamoylase activity renders these analogues into decarbamoyl analogues. Other compounds with PST-like characteristics have been detected in bivalves from Angola, Argentina and Vietnam. Today, the range of naturally occurring STX derivatives, both in marine and freshwater environments, accounts to more than fifty structural variants. This poses a problem for carrying out food safety analysis based solely in chemical methods. Fortunately, most modifications to the side chain of the tetrahydropurine core result in diminished toxicity.
Keywords: Saxitoxin; Hydroxybenzoate; M toxin; PSP; Gymnodinium catenatum ; Bivalves

Fungal metabolites: structural diversity as incentive for anticancer drug development by Hendrik Greve; Ietidal E. Mohamed; Alexander Pontius; Stefan Kehraus; Harald Gross; Gabriele M. König (537-545).
Natural products play an important role in the development of anticancer drugs. To date, predominantly metabolites from plants and bacteria served as lead structures for anticancer agents. Fungal metabolites and derivatives thereof are much less investigated for their potential in cancer therapy. There are, however, some promising candidates derived from fungi in clinical phases I and II studies. This review gives an overview on the role of natural products in cancer therapy and summarises some of the latest results of our group in this area.
Keywords: Marine fungi; Natural products; Cancer; Anticancer drugs

This paper reports the lecture delivered on the occasion of the “Ceremony of Professional Recognition” to the author at the 6th European Conference on Marine Natural Products (Porto, Portugal, 19–23 July 2009). The most recent results obtained studying opisthobranchs and diatoms at ICB are presented after a synthetic overview of the most significant moves played during this exciting 40 years game in the field of Marine Natural Products. In a symbolic manner this career is compared to a chess game. After the “romantic” opening dedicated to the study of natural black (melanin) and red-brown (phaeomelanins) pigments in the prestigious group of Rodolfo A. Nicolaus, the research on marine organisms started in 1969 and rapidly led to the characterization of an impressive number of new compounds exhibiting very unusual structures. Substantially, the “structure hunt” ended with the publication of a series of alkaloids with absolutely unprecedented structural features: the saraines. Slowly, the scientific interest shifted “from structure to function”. Opisthobranchs were selected as models to investigate. The majority of the protective allomones possessed by opisthobranch molluscs are sequestered through the food chain from algae and invertebrates. However, opisthobranchs were also able to biosynthesize many compounds structurally related to typical molecules possessed by their prey. These aspects “from function to ecology, to biosynthesis, to evolution” are discussed in detail.
Keywords: Biosynthesis; Chemical ecology; Melanins; Opisthobranchia; Porifera

Photosynthetic marine organisms as a source of anticancer compounds by F. Folmer; M. Jaspars; M. Dicato; M. Diederich (557-579).
Since early human history, plants have served as the most important source of medicinal natural products, and even in the “synthetic age” the majority of lead compounds for pharmaceutical development remain of plant origin. In the marine realm, algae and seagrasses were amongst the first organisms investigated by marine natural products scientists on their quest for novel pharmaceutical compounds. Forty years after the pioneering work in the field of marine drug discovery began, the biodiversity of marine organisms investigated as potential sources of anticancer, anti-inflammatory, and antibiotic compounds has increased tremendously. Nonetheless, marine plants are still an important source of novel secondary metabolites with interesting biomedical properties. The present review focuses on the antitumour properties of compounds isolated from marine algae, phytoplankton, mangroves, seagrasses, or cordgrasses. Compounds produced by marine epi- or endophytic fungi are also discussed.
Keywords: Cancer; Marine plants; Natural products; Phytoplankton; Symbionts