BIOACTIVE COMPOUNDS FROM MARINE ORGANISMS

Marine bioactive compounds are organic compounds produced by microbes, sponges, gorgonians, soft and hard corals seaweeds, and other marine organisms. These products are the current interest of industry for new drugs and chemicals. Marine microorganisms form highly specific and symbiotic relationships with filter-feeding organisms like sponges, alcyonarians, ascidians and marine plants. The host organism synthesizes these compounds as non-primary or secondary metabolites to protect themselves and to maintain homeostasis in their environment.

• A diverse array of bioactive compounds can be isolated from the extracts of marine organisms.

• Many of them have novel chemical structures which may lead to the development of entirely new drugs and therapeutic agents.

• Anti-cancer agents have been isolated from algae, sponges, jellyfish, corals, shark cartilage and shellfish.

• The Pacific oyster contains a substance which may help diabetics by promoting the secretion of insulin.

• Chemicals found in sponges may be used to treat yeast and fungi.

• A poison emitted by the cone snail has been found to prevent brain damage in animals after a head injury or stroke, and offers great promise in future applications in humans.

1. Marine bacteria• It has been demonstrated that marine bacteria produce

anti-microbial substances. • The first documented identification of a bioactive marine

bacterial metabolite was the highly brominated pyrrole antibiotic, isolated from a bacterium obtained from the surface of the Caribbean Sea grass Thalassia.

• This metabolite was identified by x-ray crystallographic methods, which composed of more than 70% bromine by weight.

• The metabolite exhibited impressive in vitro antibiotic properties against Gram-positive bacteria, with minimum inhibitory concentration (MIC) ranging from 0.0063 to 0.2 g/ml.

• However, it was inactive for Gram-negative bacteria and animal assays.

• It is becoming abundantly clear that bacteria form highly specific, symbiotic relationships with marine plants and animals.

• Experience in this area arose from a study of the pathogen resistance of the estuarine shrimp Palaemon macrodactylus.

• The eggs of P. dactylus possess significant bacterial epibionts, which, when removed by treatment with antibiotics, leads to the rapid infestation of the eggs by pathogenic fungi, especially of Lagenidium callinectes.

• It could be due to the anti-fungal agents produced by bacteria.

2. Marine fungi• Although terrestrial fungi have represented a major

biomedicinal resource (e.g., penicillin from Penicillium), studies to develop the biomedicinal potential of marine fungi were less.

• The isolation of a small lactone, leptosphaerin from Leptosphaeria oraemaris demonstrated that marine fungi may form important resource for unique metabolites.

• Later, the useful chemical, Gliovictin was isolated from marine fungus, Asteromyces cruciatus.

• Since then more than twenty useful bioactive compounds have been derived from marine fungi.

3. Marine microalgae• Marine microalgae are relatively unexploited but rich

resources for bioactive compounds. • Toxins initially isolated from fish or shellfish were

found to originate from microalgae, especially dinoflagellates.

• These toxins are useful tools to investigate the structure and function of ion channels on cell membranes or to elucidate the mechanism of tumor promotion based on their specific inhibitory action against protein phosphatases.

• The number of antifungal or antitumoral substances of microalgal origin is rapidly increasing.

• More importantly, structural similarities have been found between many bioactives found in marine invertebrates and those in freshwater blue-green algae.

• The similarities point to a great potential of marine blue-greens, the least explored resource, for producing bioactive compounds of medicinal value.

• Microalgae are significant resource for bioactive metabolites, particularly cytotoxic agents with applications in cancer chemotherapy.

• From the marine microalgae such as from the blooms of Phaeocystis sp., antibiotic substances were listed.

• P. pouchetii is reported to produce chemicals such as Acrylic acid, which constitutes about 7.0% of the dry weight.

• The antibiotic substances thus produced are transferred throughout the food chain and found in the digestive tract of Antartic penguins.

• Production of ß carotene and vitamins by the halotolerant alga Dunaliella sp., is documented.

• Microalgae produce incredibly potent alkaloidal neurotoxins such as saxitoxin and polyketide neurotoxins such as the brevetoxins.

4. Marine macroalgae• Of the total marine algae so far evaluated, about

25% showed one or the other biological activity. • The metabolites of green algae were reported to

contain 1,4 –diacetoxic butadiene moiety, which exhibited icthyotoxic property.

• Among the red algae, halogenated lipids have been isolated, particularly from the Laurencia sp.

• The rare chemical prostaglandin was also reported to occur in Gracilaria pichenoids.

• Ulva meal supplementation was found to provide disease resistance to red sea bream in Japan.

• Similar results were also reported from Japan on the use of Ulva meal supplementation towards disease resistance and high growth rate in black sea bream.

• The polysaccharide fractions from marine algae, Porphyra yezoensis was found to stimulate the in vivo and in vitro murine phagocytic function.

• The purified fractions gave stronger phagocytic activity. Some of the macro algal crude extracts indicated their potential therapeutic nature when challenged with potential pathogens among fish and shellfish.

5. Marine sponges• Chemicals found in sponges may be used to treat yeast and

fungi.• The wider biosynthetic capability of sponges could be

attributed to their biological association with other symbionts.

• About 38% of the sponge body comprises of microorganisms.• A wide variety of secondary metabolites were isolated from

sponges and these have been associated with antibacterial, antimicrobial, antiviral, antifouling, HIV-protease inhibitory, HIV reverse transcriptase inhibitory, immuno-suppressent and cytotoxic activities.

• In addition to potential anticancer applications, the bioactive compounds of sponges have a myriad of activities ranging from antibiotic activity including anticoagulant, antithrombin, anti-inflammatory, as well as imunomodulatory activities.

• The fact that the psammaplins have been isolated from a diversity of sponge “sources” and that brominated aromatic amino acid derivatives are common in marine bacteria suggests that these metabolites may actually derive from biosynthetic pathways of microorganisms living in association with sponges.

• Presence of specific symbiont morphologies of bacteria within specific sponges has been reported.

• These specific bacteria, which live symbiotically with sponges, passed through their feeding chambers without being digested.

• This suggested some sort of encapsulation or recognition process.

• In the demosponge, Halichondria panicea, an association with the microbe Pseudomonas insolita was suggested to be lectin-based.

• In the case of halichondrin, the exciting anticancer potential of this “sponge” metabolite has fueled an innovative chemical synthesis approach.

• Marine animals have yielded cardiovascular-active substances, and these include histamine and N-methylated histamines of sponges, viz. Verongia fistularis; asystolic nucleosides from the sponge, Dasychalina cyathina; and the nucleoside, spongosine, isolated from Cryptotethya crypta.

6. Sea Anemones• In a 1977 conference on “Drugs and Food from the Sea :

Myth or Reality,” “researchers described cardiotonic polypeptides from sea anemones .

• The sea anemone, Anemonia sulcata is a well-known natural source of supply of biologically active polypeptides.

• So far, five toxins, ATX I, II, III, IV and AS V, several polyvalent protease inhibitors, an elastase inhibitor, two blood pressure-depressive polypeptides have been isolated from it.

• The sea anemone toxins (especially toxin II of A. sulcata, ATX II) are very important tools in neurophysiological and pharmacological research.

7. Ascidians • Ascidians synthesize bioactive substances which are

cytotoxic.

8. Tunicates• Rinehart et al. (1981) have described antiviral and

antitumor depsipeptides from a Caribbean tunicate. • The tunicate of the Trididemnum genus, when extracted

with methanol-tolulene (3:1), showed activity against herpes simplex virus, type I, grown in CV-1 cells (monkey kidney tissue), indicating that the extract inhibited the growth of the virus.

• This antiviral activity may also involve antitumor activity.• When tested against other viruses, essentially all extracts

of the tunicate collected at a number of sites showed activity in inhibiting both RNA and DNA viruses.

• The suggestion that the extracts might also have antitumor properties was evidenced from their high potency against L1210 murine leukemic cells.

• Didemnin B, a cyclic antiproliferative depsipeptide isolated from the Caribbean tunicate Trididemnum solidum, was the first marine natural product to enter clinical trial as an antitumor agent.

• It showed antitumor activity against a variety of models and has been investigated in phase II clinical trials for the treatment of breast, ovarian, cervical, myeloma, and lung cancers.

• Didemnin B inhibits the synthesis of RNA, DNA, and proteins and binds noncompetitively to palmitoyl protein thioesterase.

9. Sea Hares • In the early 1970s, the extremely potent anticancer

properties were reported from the extracts of sea hare Dolabella auricularia.

• However, due to the vanishingly small abundance of the active principle ( 1.0 mg/100 kg of collected ∼organism), the structure elucidation of dolastatin 10 took nearly 15 years to complete.

• The low concentrations of dolastatin 10 in sea hares implicates a cyanobacterial diet as the origin of this bioactive secondary metabolite, and this was subsequently confirmed by direct isolation of dolastatin 10 from field collections of the marine cyanobacterium Symploca.

Marine Toxins • A toxin is a substance possessing a specific functional

group arranged in the molecule (s) and showing strong physiological activity.

• A toxin has the potential to be applied as a drug or pharmacological reagent.

• Even if direct use as a drug is not feasible because of potent of harmful side effects, the toxin can serve as a model for synthesis or improvement of other drugs.

• Many attempts have been made to develop useful drugs from the sea by screening for anticarcinogenic, antibiotic, growth-promoting (or inhibiting), hemolytic, analgetic, antispasmodic, hypotensive, and hypertensive agents.

• Tetrodotoxin, the main action of which is paralysis of peripheral nerves, is a valuable pharmacological reagent.

• Because it inhibits specifically the sodium permeability of nerve membranes, it has been valuable for elucidating the excitation mechanism.

• Insecticide developed from nereistoxin are widely marketed.

• Fishermen are familiar with the fact that flies die when they come into contact with the dead marine annelid, Lumbrinereis (Lumbriconereis) brevicirra, commonly used as bait.

• A new insecticide was developed from nereistoxin that was active against the rice stem borer and other insect pests, it does not appear to be toxic to warm blooded animals, and resistant strains of insects do not readily develop.

• Marine toxins show great promise not only as pharmacological reagents, but also as models for the development of new synthetic chemicals.

• Recently ciguatoxin, palytoxin and halitoxin have also been investigated and provide interesting new information.

• Ciguatera is a human disease caused by the ingestion of a wide variety of coral reef fishes that contain toxins accumulated via the marine food web.

• The principal toxin of ciguatera poisoning is a heat-stable, lipid-soluble compound named ciguatoxin.

• Origin of the toxin is not yet fully understood but may be derived by the fish from ingestion of toxic tropical red tide dinoflagellates such as Pyrodinium bahamense.

• Halitoxin, a toxic complex of several marine sponges of the genus Haliclona, has been isolated, partially purified, spectrally characterized, and chemically degraded, yielding a proposed chemical structure for the toxin.

• The toxin has proved to be a complex mixture of high molecular weight and toxic pyridinium salts, and can be isolated from the sponges, Haliclona rubens, H. viridis, and H. erina.

• The sponge extracts are toxic for fish and mice.

• Lophotoxin, a new neuromuscular toxin isolated from several Pacific gorgonians of the genus Lophogorgia, has been isolated and purified.

• Lophotoxin inhibits nerve-stimulated contraction without affecting contraction evoked by direct electrical stimulation of the muscle.

• The data suggest that epoxylactone and furanoaldehyde groups may be responsible for the potent biological properties of lophotoxin.

• Palytoxin, an extremely poisonous, water-soluble substance from marine coelenterates belonging to the genus Palythoa.

• Palytoxin influences calcium and potassium ion transport in nerves and the heart.

• Animals undergo paralysis and heart failure.• Palytoxin is synthesized by a marine Vibrio

sp. growing symbiotically with the coelenterate Palythoa and apparently related to Vibrio cholerae.

• Several marine organisms have provided useful drugs : liver oil from some fish provides excellent sources of vitamins A and D.

• Insulin has been extracted from whales and tuna fish; and the red alga, Digenia simplex, has long been used as an anthelminthic.

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