Drug Discovery from the

Marine ecosystems in particular have been demonstrated to be a wide source of biological and chemical biodiversity [18] (Fig. 3). Such chemical diversity will inevitably lead to new potential drug candidates [19, 20]. The reasons for this chemical diversity can be partially found in the following points [21]: (i) two-thirds of the planet is covered by the sea; (ii) life started in the sea 3.500 million years ago (on earth, only 600 million years ago); (iii) sea-water life conditions (pH, salinity, pressure, light, etc) create unique mechanisms of chemical defense; (iv) most marine organisms probably have not yet been described or have not been examined

Fig. 3. The sea as a source of new drugs

Fig. 3. The sea as a source of new drugs

chemically; (v) natural products from marine invertebrates often have structures unlike those of compounds from terrestrial organisms; and (vi) more than 1% of marine organisms present pharmacological activity. However, we are probably far from understanding what these compounds do for the organisms that produce them, or what they might do for us, and this will require a whole new chemical vocabulary from the marine environment that has yet to be learned.

The past decade has witnessed a dramatic increase in the number of preclinical lead compounds of diverse marine life entering human clinical trials [22] It is pertinent to consider the evolution of the field of drug discovery of marine natural products in this context as it may help to identify future avenues which will be even more successful. However, it is encouraging to note that during recent months the first three marine products have arrived on the market, thereby demonstrating the "proof-of-concept" that the marine ecosystem is a source of new pharmaceutical compounds.

The Spanish company PharmaMar (Madrid, Spain) has launched Yondelis (trabectedin; ET-743), a three-fused tetrahydroisoquinoline ring member of the ecteinascidins isolated from the Caribbean tunicate Ecteinascidia turbinata, for the treatment of soft tissue sarcomas; Marinomed (Vienna, Austria), an Austrian biotech company, has received market authorization for a marine biopolymer, Car-ragelose, to treat the common cold; and the Israeli company Elan Pharmaceuticals (Dublin, Ireland) has received market authorization for Prialt (ziconotide) which, being a peptide, is a novel nonopioid, nonlocal analgesic, developed for the treatment of severe chronic pain (see Fig. 4 for chemical structures of these compounds).

PharmaMar is a world leading biopharmaceutical company committed to advancing the treatment of cancer through the discovery and development of new marine-derived medicines. PharmaMar has four novel compounds in clinical development, two of which are peptides. Kahalalide F is a depsipeptide isolated from the sea slug Elysia rufescens. The final elucidation of the structure and the synthetic

Me O

Yondelis

H-CKGKGAK(jSRLMYACCTG S^RSGKC-NH

Yondelis

\CHOHo

Prialt

OSO3" Carragelose

OSO3" Carragelose

Prialt

Fig. 4. Marine-based drugs: Yondelis (PharmaMar, Madrid, Spain); Prialt (Elan Pharmaceuticals, Dublin, Ireland); Carragelose (Marinomed, Vienna, Austria)

process of this compound were set up by our group in collaboration with PharmaMar [23]. Kahalalide F is a National Cancer Institute COMPARE-negative compound which induces oncosis and it has a 5- to 40-fold greater effect on cancer cells than on healthy cells. The mechanism of action of Kahalalide F does not affect the nuclear structure of the cancer cell, while the integrity of crucial organelles such as mitochondria, endoplasmic reticulum, and lysosomes is severely compromised. The alterations found indicate that the osmotic balance of the cell may be altered, possibly as a result of cellular membrane damage. Thus, it appears that Kahalalide F does not induce apoptosis, is caspase-independent, and is not affected by DNA expression. Patient recruitment has concluded for three phase II studies to assess Kahalalide F's efficacy and safety profile in patients with solid tumors (hepatocellular carcinoma, advanced malignant melanoma, and non-small-cell lung cancer). The results are currently being analyzed to decide on the strategy to be applied in the future. In parallel to the oncology studies, recruitment has been completed for a controlled pilot phase II trial to assess the efficacy and safety of Kahalalide F in patients with severe psoriasis. The data are currently being evaluated. Aplidin (plitidepsin) was originally isolated from the tunicate Aplidium albi-cans and is currently being obtained by total synthesis; this drug was also developed by our research group in collaboration with PharmaMar [24]. The mechanism of action of Aplidin is still under investigation. This compound induces apoptosis rapidly and persistently, blocks the secretion of vascular endothelial growth factor 1 (VEGF1), and blocks the cell cycle. Aplidin (designated as an orphan drug by the European Commission and the FDA), is currently in phase II clinical trials for the treatment of solid and hematological malignant neoplasias such as multiple myeloma, T-cell lymphoma, and myelofibrosis, as well as solid tumors such as melanoma. Likewise, it is in a phase I trial for the treatment of acute pediatric leukemia.

One of the main problems associated with the use of peptides and other natural products as therapeutics is their poor pharmacokinetic properties. A strategy for improving these properties is through their chemical modification. As an example, the ongoing work that is being carried out at our laboratories on thiocoraline and lamellarin is discussed.

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