New natural products from the marine source

About 70% of our globe is covered by oceans. The oceans are full of living organisms and contain more flora and fauna compared to the land.³⁶ Marine natural products are mainly derived from marine sponges, also from corals, snails, mussels, tunicates, fungi, marine algae, bacteria etc. In the course of evolution, marine organisms have adapted excellently to the marine environment, such as high salt concentration, low temperature, high pressure and low nutrient availability. These extreme conditions require unique adaptation strategies leading to new natural products, which differ from known structures of terrestrial organisms. For example, the carbonimidic dichloride functionality (-N=CCl2) and the sulfamate group (-OSO2NHR) have only been found in marine natural products.³⁷ Moreover marine natural products comprise all chemical classes of natural products. Even though marine organisms are difficult to cultivate and normally have a low productivity, the novel compounds are very attractive as lead structures or with their potent biological activity. Furthermore these difficulties will be resolved by an increasing knowledge about them or by the application of biotechnology, combinatorial chemistry or combinatorial biosynthesis.

To resolve the problem of low concentration and limited natural sources, many research groups use different ways to get a sufficient amount of a needed natural product.

Halichondrin B (6), a polyether macrolide, was first isolated from the sponge Halichondria Okadai as the most potent member of a series of related antitumor compounds.³⁸ But because of its low concentration in the ranges of 10^-5 − 10^-6 % in sponges, it is impossible to collect enough biomass. A total synthesis involves many steps with low yields.³⁹ Therefore the mass cultivation of the macroorganism, i.e. the sponge Lissodendoryx sp., has been first established for pharmaceutical purposes.⁴⁰

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Ecteinascidin 743 (7)⁴¹ was discovered in a marine animal tunicate and contains a novel skeleton of 9 cycles based on tetrahydroisoquinoline. Its activities are orders of magnitude more potent than any other tetrahydroquinolines against B16 melanoma. The exciting aspect of 7 is its unique mode of action, constituting a new subclass of antitumor agents that could be active against resistant cell lines. Currently it is in phase II clinical trials in the United States.⁴²

Symbiotic and endophytic microbes associated with terrestrial and marine macroorganisms were supposed to be responsible for metabolites in their hosts. A mounting body of evidence suggests that many marine natural product chemicals are not produced by the source invertebrate, but rather attributable to symbiotic microorganisms living within the tissues of

the invertebrate. The studies on their collection have a considerable meaning, because it is easier to get mass production from cultures of microorganisms than from macroorganisms.

Bryostatin 1 (8) is the first potent anticancer compound of marine origin. It is a member of the large polyketide family, which are of biomedical importance. 8 was isolated in very small amount (0.00014%) from the sponge bryozoan Bugula neritina in the 1970s⁴³ and its structure was determined by X-ray crystallography in 1982.⁴⁴ It is currently in phase II clinical trials. Supply of material is always the problem by marine natural products. Whether aquaculture could supply enough material for commercial exploitation of 8 is not known. But there is increasing evidence for an important role of the bacterial endosymbionts in the bryostatin-producing B. neritina.⁴⁵ This opens a way for biotechnological manipulation of the biosynthetic genes.⁴⁶ Wender et al. have prepared a simplified analog of 8 that retains the biological activity.⁴⁷ From a commercial viewpoint, the synthetic analog may represent a strong challenge to 8.

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Due to advances in molecular genetics, scientists fed encouraged to study marine microorganisms regardless of their low productivity. Only in 2000, 31 new natural products derived from marine bacteria.⁴⁸

Thiocoraline (9), a new sulfur-containing depsipeptide with antitumor activity produced by the marine actinomycete Micromonospora marina, isolated from a marine soft coral collected in the Indian Ocean near the coast of Mozambique. It inhibits RNA synthesis and shows a potent antimicrobial activity against Gram-positive microorganisms and cytotoxic activities with an IC50 value of nM level. This antibiotic strongly inhibits the synthesis of RNA.⁴⁹ 9 is almost exclusively an exception, which enables industrial production with about 10 mg/L yield among marine drug candidates. It is now in preclinical development at PharmaMar S. A.

in Spain.

Many living organisms, especially sea creatures, produce a wide range of poisons, and these are constantly being screened for possible uses as anticancer agents. Sea squirts - a group of marine invertebrates - produce a range of chemicals, some of which have pharmaceutical potential. When the researchers isolated actinomycetes from sea squirts, and grew them in fermentation vats, they discovered a previously unidentified strain that generates a substance highly active against tumor cells. They defined the bacterium as Micromonospora lomaivitiensis and named its active components as lomaiviticin A (10) and B. These compounds also act as antibiotics and show activity against Staphylococcus aureus, one of the virulent, antibiotic-resistant bugs that cause infection and death in surgical treatments. Its MICs of tumor cells are lower than 10 pg/mL.⁵⁰

Although the research on marine natural products has going on for only about 40 years, over 5,000 compounds have been published.⁵¹ Many of them possess unique functional groups or skeletons and also potent biological activities. It is noteworthy that presently published new compounds are almost exclusively found in marine organisms. Some of them got already into preclinical phase and will lead to pharmaceutical products.⁵² Exploring marine organisms will be one of the main focuses in the next years and should be highly successful.