More than 70% of our planet's surface is covered by oceans and life on earth has its origin in the sea. In certain marine ecosystems, such as coral reefs or the deep sea floor, experts estimate that the biological diversity is higher than in tropical rain forests. Many natural products are isolated and £1.6 million centres are working to develop new drugs from our seas' natural resources
Most of these molecules are still in preclinical or early clinical development but some are already on the market, such as cytarabine or are predicted to be approved soon, such as ET743 (YondelisTM). a-conotoxins are calcium-channel blockers, ß-conotoxins are potassium-channel blockers and µ-, as well as ?-conotoxins, are sodium channel blockers, investigating their potential use as adjuncts in anaesthesia, analgesics or as drugs for the treatment of conditions such as epilepsy, cardiovascular disease and psychiatric disorders. The strong commercial interest in these molecules is reflected by more than 100 patents and patent applications with the word 'conotoxin(s)' in their title. main players in the field of conotoxin commercialization are Cognetix, Neurex, AMRAD and Xenome. Ziconotide, previously referred to as CI1009 or SNX111, is the synthetic form of a-conotoxin MVIIA, a neuron-specific, N-type calcium-channel blocker and the first conotoxin drug to receive an approval letter from the FDA.
Ziconotide was developed by Neurex as an intrathecal treatment for chronic pain. Unlike morphine it does not induce the development of tolerance, constipation or respiratory suppression. Another a-conotoxin, AM336, is in clinical development at AMRAD for the treatment of severe morphine- resistant pain. This molecule was found to be 100-fold more selective than Ziconotide for N-type over P/Q-type calcium channels with reduced adverse neurological effects, which suggests that it may be preferable to Ziconotide Conus magus. This cone snail paralyses its prey using a poison-tipped barb (right). The poison is a painkiller many times more potent than morphine, and is now on the market as Prialt.
GTS21, 3-(2,4-dimethoxybenzylidene)-anabaseine, is a selective 7 nAChR partial agonist in clinical development at Taiho to treat Alzheimer's disease and schizophrenia. GTS21 was isolated from the nemertine worm Amphiporus lactifloreus. The compound has been shown to improve learning performance and memory retention in passive avoidance models in nucleus basalis magnocellularis (NbM)-lesioned rats as well as in active avoidance models in aged rats. It also reduced neocortical cell loss in NbMlesioned rats and cell death induced by a-amyloid or glutamate in cultures of neuronal cells Bugula neritina, has been the source of a family of protein kinase C (PKC) inhibitors called bryostatins currently in clinical trials for cancer. Bryostatin-1 has been granted Orphan Drug status by the FDA and has been designated an Orphan Medicinal Product in Europe for oesophageal cancer in combination with paclitaxel
Hymenialdisine is a sponge alkaloid named after Hymeniacidon aldis. The compound inhibited the in vitro phosphorylation of human microtubule-associated protein tau, which is implicated in the pathogenesis of Alzheimer's disease, and in Sf9 cells expressing the protein. Additionally, the molecule reduced the production of interleukin-8 and prostaglandin E2 in human cells, indicating that it may have anti-inflammatory activity.
Scytonemin was found to inhibit human pololike kinase (IC50?2 ?M), which has an important role in the regulation of mitotic spindle formation as well as other kinases involved in cell cycle control, including checkpoint kinase 1 and CDK1.
It has been suggested that scytonemin may provide a novel pharmacophore for the development of protein kinase inhibitors as antiproliferative and anti-inflammatory drug.
Aplidium albicans. Another anticancer drug has been isolated from this sea squirt. PharmaMar calls it Aplidin and is testing its efficacy.
?eleutherobin, a diterpenoid, from the soft coral Eleutherobia sp; sarcodictyins, diterpenoids, from the Mediterranean coral
?Sarcodictyon roseum; dolastatins, short peptides containing unique amino acids, from the sea hare Dolabella auricularia , a nudibranch snail and, later, from marine cyanobacteria
?halichondrin B a polyether macrolide from the sponge Halichondria okadai
?laulimalide, as well as its rearrangement product isolaulimalide, which are 18-membered macrocyclic lactones, from the sponge Cacospongia mycofijiensis
?peloruside A, related to bryostatin 1, from the sponge Mycale sp.
?hemiasterlins, tripeptides from the sponges Auletta sp. and Siphonochalina sp.
?vitilevuamide a bicyclic marine peptide, from the ascidians Didemnum cuculiferum and Polysyncraton lithostrotum
All of these compounds have been reported to have general cytotoxic activity and to kill cancer cells in vitro but only dolastatin 10, the dolastatin 15 analogues ILX651 and cemadotin, discodermolide and the hemiasterlin analogue HTI286 have so far reached clinical development. Halichondrin B analogues are in preclinical development at Eisai. The laulimalides and discodermolide are of special interest to anticancer drug discovery researchers because they have been shown to remain active in cells over expressingg multidrug-resistant P-glycoprotein.
Corey and his student Eduardo Martinez designed a structurally simpler, easier to synthesize and more stable analogue of ET743 named phthalascidin (PT650). PT650 and ET743 show undiminished potency in cell lines resistant to the topoisomerase inhibitors camptothecin and etoposide ET743 has completed clinical trials for soft-tissue sarcoma and is currently under regulatory review in Europe for the treatment of this type of cancer for which it was granted Orphan Medicinal Product designation by The European Agency for the Evaluation of Medicinal Products in 2001.
Ecteinascidia turbinata, a Caribbean and Mediterranean sea squirt, makes a compound that PharmaMar has brand-named Yondelis. The firm is awaiting marketing approval from the European Medicines Agency for this antitumour compound for soft-tissue sarcomas. Trials are also under way for ovarian cancer.
In the same year, Zeltia, the parent company of PharmaMar, announced a licensing agreement with Ortho Biotech, a Johnson and Johnson subsidiary, to develop and market ET743. A comprehensive development programme to study the potential use of ET743 for the treatment of other forms of cancer was agreed. So far, promising results have been released from phase II clinical trials for ovarian and breast cancer. The efficacy of ET743 in endometrial and non-small cell lung cancer is also being investigated in phase II trials. To date, more than 1,600 patients have been treated with ET743.
The author is Research Scientist-1, AstraZeneca India Pvt Ltd , Bangalore