Marine Natural Products: a prolific source of new leads in drug discovery

The huge amount of money spent for drug discovery all around the world is not producing a correspondingly high number of new drugs. The chemical diversity of the available libraries has been extensively explored, and there is a clear need of new structural diversity. Here the biodiversity of marine environment can be of help. This is particularly true for marine invertebrates, whose extensive biodiversity is very often paralleled by a comparable chemical diversity of their secondary metabolites. Marine invertebrates have been and continue to be a prolific source of novel and structurally diverse natural products, many of them showing potent and selective bioactivities that trigger biomedical interest. A variety of limiting factors has affected until now the full exploitation of bioactive natural products from marine invertebrates, the most important being the supply problem. The complex structure of most natural products usually prevents their large-scale total synthesis, while a massive collection of the organisms producing compounds of industrial interest appears unrealistic. However, the realization that many of the metabolites from marine invertebrates are produced by very specific symbiotic microorganisms, and the upcoming possibility to transfer the biosynthetic pathways to microorganisms more amenable to cultivation appear to be a promising solution to the supply problem. Over the last 15 years, our research group’s interest has been focused on the chemical study of Caribbean marine sponges as a source of new structures to be used as leads in the search of new drugs. Caribbean Ocean is one of the few epicenters of marine biodiversity in the world, and sponges are an important component of marine biodiversity. These colorful animals living in the tropical oceans are well-known to produce a large array of new chemical structures with promising anti-cancer, anti-inflammatory, immunomodulating and anti-bacterial properties. The efforts of our research group are directed to explore the powerful biodiversity potentialities of these animals studying their chemistry and, at the same time, to pursue a biotechnological approach for the inexpensive and reproducible production of marine natural compounds. Recent results obtained studying the chemistry of the Caribbean sponges Pseudaxinella flava and Tedania ignis will be presented in this communication. From the liphophilic extract P. flava three diterpene isonitriles were isolated. The compounds have been first screened for their in vitro growth inhibitory activity (MTT assay) using four human cell lines. Then, the gross mechanism of action of the isonitriles have been determined by means of computer-assisted phase contrast videomicroscopy analysis. The digital movies shoved that the cancer cells treated with isonitriles are pro-autophagic agents and make the cells unable to undergo mitotic processes, resulting in a cytostatic effect. The anti-inflammatory activity of tedanol will then discussed. Tedanol is a new brominated and sulphated diterpene alcohol having a pimarane skeleton, isolated from the Caribbean sponge T. ignis. Tedanol showed a significant anti-inflammatory in vivo activity at 1 mg/kg3, coupled with the inhi-bition of the COX-2 expression. This activity makes tedanol a novel potent COX-2 selective inhibi-tor, and could represent an excellent water-soluble anti-inflammatory molecule with minimal gas-trointestinal toxicity.