Highlights of marine natural products chemistry (1972–1999) D. John Faulkner Scripps Institution of Oceanography University of California at San Diego La Jolla CA 92093-0212 USA Received (in Cambridge) 12th November 1999 Covering 1972–1999 1 Highlights of marine natural products chemistry (1972–1999) Marine Natural Products Chemistry is essentially a child of the 1970’s that developed rapidly during the 1980’s and matured in the last decade. With a few notable exceptions it is difficult to select individual papers that significantly impacted the field. However marine natural products chemistry has often influenced other fields and that aspect is the focus of this review. It is clear that the early directions taken by marine natural products chemists drew as much from the examples provided by insect chemical ecology as from the longer history of phytochemistry.By 1975 there were already three parallel tracks in marine natural products chemistry marine toxins marine biomedicinals and marine chemical ecology. It is the integration of the three fields of study that has given marine natural products chemistry its unique character and vigour. Studies of marine toxins have been dominated by Japanese researchers.1,2 Although the structures elucidated have grown larger and larger the polyether structural class remains the basis of a majority of marine toxins. The ‘ladder-like’ skeleton of the polyether toxins was established in 1981 by an X-ray crystallographic study of brevetoxin B 1 from the dinoflagellate Gymnodinium breve.3 Ciguatoxin 2 the principal toxic constituent in ciguateric seafood poisoning was identified in 1989 from material extracted from Pacific moray eels (Gymnothorax javanicus),4 but congeners were isolated from the epiphytic dinoflagellate Gambierdiscus toxicus,5 demonstrating the importance of the marine food chain in seafood poisoning.2 From the same source maitotoxin 3 the largest and possibly the most lethal non-proteinaceous toxin was identified in a tour de force of modern structural elucidation.6,7 Of equal importance and complexity the structural elucidation of palytoxin 4 a complex polyol isolated from the zoanthid Palythoa toxicus provided a classical example of the use of both spectroscopy and synthesis D.John Faulkner born in England in 1942 received his B.Sc.and Ph.D. degrees from Imperial College London where he studied synthetic organic chemistry under the guidance of Sir Derek Barton. He received postdoctoral training from R. B. Woodward at Harvard University and W. S. Johnson at Stanford University before joining the faculty of the Scripps Institution of Oceanography University of California at San Diego in 1968. Recognizing the need to ‘do something more marine’ he began a new career in marine natural products chemistry which has spanned the entire period of this review. He is currently Professor of Marine Chemistry. This journal is © The Royal Society of Chemistry 2000 MILLENNIUM REVIEW in structural elucidation.8–10 Unfortunately the tremendous impact of the palytoxin and maitotoxin studies had the effect of making studies of smaller toxic molecules seem less challenging which is far from the truth.The increasing frequency of toxic algal blooms and the associated shellfish contamination ensures that studies of marine toxins will continue to be of importance well into the next century and probably for as long as human consumption of seafood continues. Research on bioactive compounds from marine organisms has provided the bread and butter support of marine natural products research throughout the past quarter century. Although none of the discoveries has yet led to a pharmaceutical product there is hope that one or more of the many marine natural products currently under investigation will eventually do so.11 Since the current status of marine biomedical research has been a popular subject for many recent reviews,12 just a few examples will be highlighted here.Among the anticancer compounds currently under investigation bryostatin 1 5 serves as a good example of past and current trends in marine biomedical research. Bryostatin 1 5 was isolated in very small quantities from the bryozoan Bugula neritina in the 1970’s and its structure was determined by X-ray crystallography in 1982.13 It is currently in phase 2 clinical trials. Supply of material for clinical trials was a problem until it was demonstrated that B. neritina was amenable to aquaculture. Recently evidence favouring a symbiotic origin for bryostatin 1 5 has been presented,14 opening the way for biotechnological manipulation of the biosynthetic genes.15 Furthermore it has been shown that semi-synthetic bryostatins retain the activity of the natural product.16 Other marine natural products under intense investigation at present include the potential anticancer agents dehydrodidemnin B 6,17 dolastatin 10 7,18 ecteinascidin 743 8,19,20 halichondrin B 9,21 isohomohalichondrin B 10,22 curacin A 11,23 discodermolide 12,24 eleutherobin 1325 and sarcodictyin A 14.26 Marine organisms have also provided a number of antiinflammatory agents such as pseudopterosins A 1527 and E 16,28 topsentin 17,29 debromohymenialdisine 1830 and scytonemin 19,31 all of which are currently under active investigation and manoalide 20,32,33 which has become a standard drug in inflammation research.An interesting commercial application of a marine product is the use of a partially purified extract of the gorgonian coral Pseudopterogorgia elisabethae the source of the pseudopterosins as an additive in cosmetic products. In addition to those compounds being considered for medicinal use there are an increasing number of compounds that are currently used as reagents in cellular biology. Examples include the sponge metabolites swinholide A 21,34 jaspamide 22,35,36 and others that act on actin ilimaquinone 23,37 which causes vesiculation of the Golgi,38 and adociasulfate 2 24,39 an inhibitor of motor proteins,40 as well as those compounds too many to list that act on individual proteins and receptors.Marine natural products chemists have always shown a great interest in the natural functions of the metabolites that they study. Compounds such as stypoldione 25 from the brown alga Stypopodium zonale41 and latrunculin A 26 from the sponge Latrunculia magnifica42 were discovered on the basis of their ichthyotoxicity and were later shown to be cytotoxic. However there are many more subtle ways in which chemicals produced by marine organisms can enhance the survival of the producing 1 Nat. Prod. Rep. 2000 17 1–6 hare Aplysia californica44 and that the sesquiterpene isonitrile 28 isolated from the nudibranch Phyllidea varicosa was a metabolite of the sponge Hymeniacidon sp.,45 led to the hypothesis that the shell-less molluscs had evolved by loss of the shell after the ancestral mollusc had acquired defensive organism.Studies of the feeding deterrence caused by algal metabolites have established chemical defense as an important factor in reducing predation.43 The discovery that red algal metabolites such as the polyhalogenated monoterpene 27 were selectively stored in the midgut gland and the skin of the sea Nat. Prod. Rep. 2000 17 1–6 2 chemicals of dietary origin.46 The observation that many nudibranchs sequestered metabolites of sponges and tunicates implied that these constituted chemical defenses of the producing organisms a hypothesis that is currently being tested.47 Another rationale for chemical production in sessile organisms is that the metabolites inhibit settling of fouling organisms.This hypothesis has also been tested48 but the objective of using natural antifouling agents in marine coatings has yet to be realized. During the past decade many authors have acknowledged the importance of symbiosis in the marine environment and have speculated that key marine natural products were produced by symbiotic microorganisms. Although most claims lacked experimental support two metabolites of the lithistid sponge Theonella swinhoei swinholide A 21 and the cyclic peptide theopalauamide 29 were shown to be localized in a mixed bacterial fraction and a filamentous d-proteobacterium respectively. 49 Although most bacterial symbionts have defied attempts to culture them cultures of the dinoflagellate Amphidinium sp.which is a symbiont of the flatworm Amphiscolops sp. have yielded a series of very cytotoxic macrolides such as amphidinolide B 30.50 Marine organisms have provided a seemingly endless parade of novel structures. New carbon skeletons too many to be highlighted here were described with a frequency that exceeded all expectations. Several functional groups are uniquely or predominantly marine. In the early years chemists were fascinated by the small polyhalogenated compounds such as 27,51 most of which have still defied synthesis. The carbonimidic dichloride functionality of 31 and the sulfamate group in haplosamate A 32 have only been found in nature as metabolites of marine sponges.52,53 Sesquiterpene or diterpene isonitriles isothiocyanates thiocyanates and formamides exemplified by isonitrile 28 are predominantly produced by sponges.Biosynthetic studies have shown that the isonitrile carbons in diisocyanoadociane 33 can be derived from cyanide and thiocyanate ions but some details of the pathway remain 3 Nat. Prod. Rep. 2000 17 1–6 unclear.54,55 An interesting hypothesis concerning the biosynthesis of manzamine A 34 has stimulated research on related alkaloids that can be derived from cyclic bis-pyridine derivatives. 56 Unusual cyclic peptides represented by ulithiacyclamide 35 from the tunicate Lissoclinum patella,57 theonellamide F 36 from Theonella swinhoei58 and diazonamide 37 from the tunicate Diazona chinensis59 are frequently found in many marine phyla.Sesterterpenes originally found in Ircinia oros,60 represent a major group of sponge metabolites but are less often found elsewhere. These are but a few examples of the novelty of marine natural products. Nat. Prod. Rep. 2000 17 1–6 4 Although it is clear that marine natural products chemistry has had a major impact on chemistry over the past 25 years it is difficult to predict the future. 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