Lower metazoans, lesser deuterostomes, and humans

Marine organisms from all marine phyla have been a source of food since humans first began to explore marine environments. In stark contrast to terrestrial plants and animals that have been widely used for remedies of human disorders—the World Health Organization (WHO) estimates that 60–80% of the world's population relies primarily on plants for their basic health care—only a small number of marine species have been used for medicines, mostly due to human's limited access to marine resources.

Perhaps the earliest industrial application of components of marine organisms is Tyrian purple or royal purple, a brilliant dye produced from marine gastropods (protostome) of the superfamily Muricacea, which dates back to 1600 b.c. Phoenicians processed the dye from the mucus in the hypobrachial glands of such mollusks as Murex trunculus at many dyeing factories located on the coast of Lebanon. However, only 0.03 oz (1 g) of the dye could be obtained from 10,000 animals and was worth as much as 0.35–0.7 oz (10–20 g) of gold. Actually, the mucus contained in the hypobranchial glands is colorless, which turns purple by enzymatic, oxidation, and photochemical reactions during processing.

Regarding the medicinal application of marine organisms, though, there were only a few examples, including using the red alga, Digenea simplex, to treat ascariasis in Asian countries. No one had seriously thought about this issue until the early 1950s when a professor at Yale University discovered unusual nucleosides, spongouridine and spongothymidine, from the Caribbean sponge, Tectitethya crypta (=Chryptotethya crypta); these nucleosides are composed of arabinose in place of ribose or deoxyribose found in those of RNA or DNA. This discovery was unprecedented and impressed researchers with the uniqueness of marine metabolites. Nearly 15 years later, Ara-A (arabinosyl adenine) and Ara-C (arabinosyl cytosine), antiviral and anticancer drugs, respectively, were developed from these sponge-derived nucleosides. Obviously, this development was the most significant driving force for organizing the symposium entitled "Drugs from the Sea," which was held at University of Rhode Island in 1967. The 1969 discovery of a large amount of prostaglandins from the Caribbean gorgonian, Plexaura homomala further stimulated research into marine metabolites. These achievements occurred largely due to scuba diving, which allowed researchers not only to observe but also to collect exotic marine creatures.

A new research field of marine natural products was created in the early 1970s, and many researchers from academia as well as industry embarked on exploring medicinally active compounds from marine organisms. This resulted in the isolation of more than 10,000 new compounds over the next 30 years, including a number of structurally unusual and biologically interesting compounds. Clinical trials on more than 30 marine natural products and their derivatives have since been conducted.

More than any other organism, sponges have been the most actively exploited sources for drugs, because they contain

not only metabolites of unique structures, but also of potent biological activities. It is widely believed that symbiotic bacteria or other microbes are responsible for the production of biologically active sponge metabolites. In fact, sponges contain numerous compounds reminiscent of microbial metabolites (e.g., sponge peptides often embrace D-amino acids and unusual amino acids). Increasing evidence for the involvement of bacteria in production of unusual sponge metabolites has been obtained; highly unusual antifungal cyclic peptides, theopalauamides, were found to be contained in the new δ-proteobacterium Entotheonella palauensis isolated from the Palauan sponge, Theonella swinhoei.

Among sponge-derived compounds, halichondrin B, an unusual polyether macrolide originally discovered from the Japanese marine sponge, Halichondria okadai, is highly promising as an anticancer agent. However, its low contents (10% based on wet weight) and its complex structure are the most serious obstacles for the development of drugs, as is the case for other marine-derived drug candidates. Fortunately, a New Zealand sponge, Lissodendoryx sp., inhabiting depths of 279–344 ft (85–105 m) off the Kaikoura Peninsula, South Island, was found to contain larger amounts of halichondrin B and analogues. To guarantee sponge supplies required for clinical trials, aquaculture of this sponge has been initiated. Small pieces of the sponge were cultured on lantern arrays in shallow waters; small explants grew rapidly, 50-fold in six weeks in some areas. Although the bath sponges have been cultured in the Mediterranean and other regions for more than 80 years, this is the first sponge aquaculture for the production of drugs.

Another promising sponge-derived anticancer agent is discodermolide, discovered from Discodermia dissolute collected at depths of 656 ft (200 m) off the Bahamas. It causes anti-cancer activity by stabilizing microtubules, as in the case of the bestselling anticancer drug, Taxol, which is extracted from the Pacific yew tree. Again, large amounts cannot be supplied by extracting the sponge that inhabits deep sea, but its relatively simple structure indicates the possibility of chemical synthesis.

Cnidaria usually harbor symbiotic dinoflagellates that are thought to be responsible for the synthesis of cnidarian metabolites such as terpenoids. Diterpenoid glycosides called pseudopterosins, which are isolated from the Caribbean sea whip, Pseudopterogorgia elisabethae, have been added to skin-care creams because of their anti-inflammatory properties.

Opisthobranch mollusks (protostome) are unique animals that have abandoned their protective shells in the course of evolution. Instead, they have developed chemical defenses, which are extracted from their prey organisms. For example, the Spanish dancer, Hexabranchus sanguineus, extracts powerful antifeedants, trisoxazole-containing macrolides from sponges. Similarly, the sea hare, Dolabella auricularia, accumulates numbers of bioactive compounds from cyanobacteria such as Lyngbya majuscula, among which dolastatin 10, an unusual linear peptide, is highly promising as an anticancer drug (under Phase II clinical trials in 2003). Elysia rufescens, a Hawaiian sacoglossan mollusk, extracts a cyclic peptide, kahalalide F, from a green alga, Bryopsis sp. (actually derived

from an epiphytic cyanobacteria, most likely Lyngbya spp.). The peptide entered Phase I clinical trials in 2002 as an anticancer drug.

Cone snails (protostome), comprising 500 species, hunt fishes, mollusks, and worms using venomous harpoons, which is a very rare adaptation for marine animals. Unexpectedly, the venom glands contain hundreds of small biologically active peptides. For example, Conus geographus, a fish-hunting species that occasionally causes death in humans, contains peptides, tabbed conotoxins, that act on Na+ channels, Ca2+ channels, acetylcholine receptors, and others. Consequently, conotoxins are considered potential drugs for the treatment of neurological disorders. In fact, Ω-conotoxin MVIIA derived from C. magnus, an N-type Ca2+ channel blocker, is promising as a painkiller for cancer and HIV patients; it is 50 times more potent than morphine.

Colonial ascidians often contain compounds of highly unusual structures with potent biological activities, which perhaps is due to the presence of microbial symbions such as prochlorons. Ecteinascidia turbinate, which grows on man-grove roots in the Caribbean, was first reported to be highly antitumoral in 1967, but the active components were not unveiled until 1990. Interestingly, ecteinascidin 743, an active component, is closely related to saframycins, antibiotics isolated from terrestrial actinomycetes. This alkaloid is shortly expected to become the first marine anticancer drug. It should be noted that echteinascidins are likely produced by symbiotic microbe(s). The Mediterranean tunicate, Aplidium albicans, contains a depsipeptide, aplydine (dehydrodidemninB), which showed good results in clinical trials as a anticancer drug.

Cephalostatin 1, a highly unusual dimeric steroid discovered from the hemichordate, Cephalodiscus gilchristi, collected at depths of 197–262 ft (60–80 m) off East Africa, proved to inhibit the growth of P388 murine leukemia cells at incredibly low concentrations. Interestingly, closely related ritterazines were isolated from the Japanese ascidian, Ritterella tokioka, thus indicating the involvement of symbiotic microbes in synthesis of this unique dimeric steroid.

Increasing numbers of marine natural products have been found to have promising properties for the treatment of human medical disorders. Obviously, marine organisms, particularly benthic invertebrates, are an important source of drugs.

Resources

Books

Baslow, Morris H. Marine Pharmacology. Baltimore: Williams and Wilkins, 1969.

Fusetani, Nobuhiro, ed. Drugs from the Sea. Basel: Karger, 2000.

Pietra, Francesco. Biodiversity and Natural Product Diversity. London: Pergamon, 2002.

Scheuer, Paul J. Chemistry of Marine Natural Products. New York: Academic Press, 1973.

Periodicals

Faulkner, D. John. "Marine Natural Products." Natural Product Reports 19 (2002): 1–48.

Newman, David J., Gordon M. Cragg, and Kenneth M. Snader. "The Influence of Natural Products upon Drug Discovery." Natural Product Reports 17 (2000): 215–234.

Nobuhiro Fusetani, PhD