Monday, July 30, 2007 - 8:30 AM
S24
Anticancer drug discovery from marine cyanobacteria; new molecules working by new mechanisms
William Gerwick1, Wolf Wrasidlo2, Kerry McPhail3, and Eric Andrianasolo3. (1) Scripps Institution of Oceanography, University of California, San Diego, 9500 Gilman Drive, MC 0212, La Jolla, CA 92093, (2) Moores Cancer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, (3) College of Pharmacy, Oregon State University, Corvallis, OR 97331
Marine cyanobacteria are an exceptionally rich source of novel peptide and integrated peptide-polyketide type natural products. Many of these natural products are potently cytotoxic to mammalian cells, and this has furthered their exploration as a source of new anticancer lead compounds. Intriguingly, while many of these cyanobacterial natural products owe their potent biological properties to action either as antitubulin or anti-actin agents, a growing number work at novel targets. Our efforts in this area over the past 15 years have mainly revealed the exceptional capacity of these organisms to create structurally-diverse cyclic peptides and lipopeptides, several with nanomolar-level of cytotoxicity. A number of these possess a terminating N,N-dimethyl amino functionality, a feature in common with the well known cytotoxins dolastatin 10 and 15. This presentation will feature the exploration of diverse collections of marine cyanobacteria which have yielded new and ultrapotent lipopeptide natural products. From the South Indian Ocean a collection of Geitlerinema yielded a very unusual lipopeptide with a terminating cyclic aminal functionality. From the South Pacific, a series of exceptionally potent cytotoxins were isolated from the genus Lyngbya with IC50’s in the high femtomolar range to some cell lines. Collections of deep- and shallow-water species of Lyngbya and Leptolyngbya from both the Pacific and Caribbean coasts of Panama have yielded new and highly cancer cell toxic lipopeptides. On the basis of this exploration of diverse populations of marine cyanobacteria, a continued examination of this resource for new cytotoxic natural products is warranted.