Research Article: Marine Natural Products: A Way to New Drugs

Date Published: July , 2009

Publisher: A.I. Gordeyev

Author(s): V.A. Stonik.



The investigation of marine natural products (low molecular weight bioregulators) is a rapidly developing scientific field at the intersection of biology and chemistry. Investigations aimed at detecting, identifying, and understanding the structure of marine natural products have led to the discovery of 20,000 new substances, including those characterized by an extremely high physiological activity. Some results and prospects of works aimed at creating new drugs on the basis of marine natural products are discussed herein.

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Low molecular natural products are largely referred to the so-called secondary metabolites. In contrast to primary metabolites, these substances are rare in occurrence and may be detected only in some taxa, and occasionally, in one biological species (subspecies, strain). They are formed on the basis of precursor substances participating in primary metabolism, such as acetic acid, amino acids, glucose and are observed mainly as final products of biochemical transformations. Secondary metabolites are quite diverse by chemical structure and include steroids, terpenoids, alkaloids, polyketides, phenolic metabolites, some carbohydrates, lipids, and peptides. On the other hand, secondary metabolites can be classified on the basis of their biological functions as hormones, antibiotics, toxins, pheromones, etc. Among the natural products there are endo-metabolites, i.e., substances exercising their biological functions in the organisms-producers, for instance, oxylipins, hormones, phytoalexins, and more numerous exometabolites released into the environment and being of ecological importance, including toxins, antibiotics, and different signal compounds.

With the use of an aqualung, natural-product chemists got a chance to study more and more marine organisms. The American scientist Werner Bergmann was one of the first to start their chemical investigation. In 1951, he reported the isolation of unusual nucleosides (spongothymidine (1) and spongouridine (2) (Fig. 1), and then others) [2-4] from the sponge Cryptotethia crypta collected near the coast of Florida. They contained arabinose residues, instead of the ribose and desoxyribose residues observed in most compounds of that class. Those investigations stimulated the appearance of the antimetabolite conception in pharmacology. Antimetabolites are the active substances of drugs, which are characterized by a significant similarity to, and structural difference from, human metabolites. Antimetabolites participate in the biosynthesis of some biopolymers, more often, of DNA, and inhibit its exhibiting antitumor and antiviral properties. Bergmann’s discovery was followed by the development of two arabinonucleoside drugs: arabinoadenine (3) (ara-A, Vidarabine) and arabinocytosine (4) (Ara-C, Cytarabine) (Fig. 1), which were used in clinical practice as antitumor and antiviral drugs for tens of years. Several other drugs of a nucleoside nature (azidothymidine, acyclovir, etc.) differ from ordinary nucleosides in other structural features. For instance, azidothymidine has an azide group in its monosaccharide residue, while acyclovir is characterized by an open furanose cycle.

The first analgesic drug based on marine natural products was called ziconotide (prialt). It was created after twenty years of investigating toxins from predatory moluscs-gastropods belonging to the Conus genus. In the end of 2004, this compound under the commercial name “prialt” was approved for production and clinical use in the USA, and a few months later, in Europe. The name “ziconotide” is more often used for its active substance, ω-conotoxin, obtained with the help of peptide synthesis.

Pseudopterosins, for instance pseudopterosin E (20) (Fig. 5), are characterized by strong anti-inflammatory action. Pseudopterosins belong to the group of diterpene glycosides isolated by Fenical and co-workers from the Caribian gorgonian coral Pseudopterogorgia elisabethae in the end of the 1980s [52]. The anti-inflammatory action of pseudopterosins is stronger than that of the well-known anti-inflammatory drug indomethacin. They influence the biochemical transformation of arachidonic acid, decreasing the synthesis of eicosanoids [53]. Estee Lauder has created a cosmetic cream for facial skin for commercial realization on the basis of partially purified extracts of P. elisabethae, containing pseudopterosin E. To ensure production of the cream with the required amount of pseudopterosins, scientists collected a lot of gorgonian corals along the coast of the Bahamas Islands and, then, studied the regeneration of corals after the removal of some parts of their colonies. Two other ways to produce pseudopterosin were developed to decrease the damage to underwater biocenoses: their aglycons were synthesized by several methods [54-56] and, then, glycosylated: moreover, scientists have discovered new biotechnological ways to produce pseudopterosin from farnesol pyrophosphate under the action of enzymes extracted from P. elisabethae [57].

After the discovery of arabinonucleosides characterized by antiviral and antitumor properties in the beginning of the 1950s and after the following synthesis of some nucleoside derivatives, which became the biologically active substances of antiviral drugs, the search for new marine antiviral drugs has been in progress. Compounds with such activity were found among terpenoids, steroids, alkaloids, aliphatic and aromatic derivatives, peptides, polysaccharides, and other secondary metabolites extracted from different marine organisms [68-71].

Two new drugs – Histochrome for ophthalmology and Histochrome for cardiology – have been created in the Pacific Institute of Bioorganic Chemistry, Russian Academy of Sciences, on the basis of sea urchin pigments characterized by antioxidant, antimicrobial and anti-inflammatory properties and then approved for production and use in Russia [74]. Histochrome for ophthalmology has proved highly effective against traumas and blood strokes of different origins and against some other eye diseases. Histochrome for cardiology is a cardioprotector reducing by half the necrosis zone formed due to acute myocardial infarction. Histochrome for cardiology commonly assigned as drop infusion 10 minutes before the thrombolytic therapy decreases the frequency of extrasystoles. Moreover, this drug decreases the number of complications after open-heart surgery. The major constituent active substance of both drugs is the well-known pigment echinochrome (31) (Fig. 8). Scientists have found an easily accessible natural source of echinochrome (the sand dollar Scaphechinus mirabilis) and have developed new methods of isolation and synthesis of this pigment with a high yield [47].

Marine natural products are quite diverse. Every year, the number of known marine natural products increases (between 2007 and 2008, almost by 1,000 compounds every year) [80]. Their biochemical diversity is a result of the high biological diversity in the seas and oceans. According to different estimates, our planet is inhabited by several million species of marine microorganisms, as well as about a million of yet undescribed species of marine invertebrates and other marine organisms.