Oct 12 2005
Researchers have discovered 10 new molecular structures with pharmaceutical potential in a species of red seaweed that lives in the shallow coral reef along the coastline of Fiji in the south Pacific Ocean.
Some of these natural compounds showed the potential to kill cancer cells, bacteria and the HIV virus, according to research at the Georgia Institute of Technology. In fact, two of them exhibit anti-bacterial activity towards antibiotic-resistant Staphylococcus aureus at concentrations worth pursuing, though researchers don't know yet whether the concentrations of the compounds required to kill the bacterium would be harmful to humans.
The compound that was isolated in the greatest abundance -- named bromophycolide A by the researchers -- killed human tumor cells by inducing programmed cell death (called apoptosis), a mechanism that is promising for development of new anti-cancer drugs, researchers noted.
The findings on three of these compounds - called diterpene-benzoate natural products -- are reported in the Oct. 12 online issue of the American Chemical Society journal Organic Letters. Information on the other compounds will be published later. The research, which is part of an environmental conservation, economic development and drug discovery project in Fiji, was primarily funded by the Fogarty International Center at the National Institutes of Health. Georgia Tech Professor of Biology Mark Hay leads the project, which also aims to benefit the Fijian government and villages, which own their local natural resources and will benefit monetarily if these natural resources become marketable drugs.
"We're only at the test-tube level so far," explained Julia Kubanek, a Georgia Tech assistant professor of biology, chemistry and biochemistry, who is the lead author on the paper. "The next step is to discover how these compounds work and then to study them in a more complex model system."
The U.S. pharmaceutical company Bristol Myers Squibb is collaborating with Georgia Tech researchers to determine how some of these 10 compounds kill cancer cells. Meanwhile, Georgia Tech has filed a provisional patent to protect the discovery of these structures and small variations of them.
"These molecular structures are curious in the way carbon atoms are attached," Kubanek said. "It's very unusual. They represent a new category of organic molecules. It's exciting as a biochemist to observe that living organisms have evolved the ability to synthesize such unique and exotic structures compared to other molecules typically produced by seaweeds."
The source of these new molecular structures is a red seaweed (Callophycus serratus) collected from four Fijian sites. Among the sites, researchers found variations in the molecular structures produced by the species.
"There are chemical differences among populations of this seaweed species, even though two of the sites where it was collected are only about 2 kilometers apart," Kubanek noted. "… This shows us there are small, but valuable differences within species, and this genetic biodiversity is important to protect as a resource for the future." Researchers have been analyzing extracts from about 200 marine plant and invertebrate animal samples they collected from the Fijian coral reef in June 2004 with the permission of the Fijian government and local resource owners.
"Marine organisms make molecules for their own purposes that we might co-opt for our own use as pharmaceutical agents," Kubanek explained. "The organisms' purposes include defense against predators, the ability to fight diseases, and the production of chemical cues, such as those used for sex recognition."
Hay, Kubanek, and their colleagues collected baseball-sized samples of reef species that exhibit unusual growth and/or behavioral phenomena. Among their collection were soft corals, marine sponges, slugs, and green, red and brown seaweeds.
In the lab, researchers extracted these organisms using mixtures of organic liquids, which opened up the cells and dissolved the natural products. The organic liquids were then removed from the extract by evaporation, and small quantities of each extract were tested against a battery of pharmaceutical drug targets, including malarial parasite, tuberculosis-causing bacteria, and several cancers.
Typically, these tests involve exposing live, disease-causing cells -- parasites, bacteria or cancer cells -- to an extract and then assessing cell death compared to cells that were not exposed to extracts. Georgia Tech scientists then prioritized further study of extracts that had strong effects on these disease-causing cells.
The Callophycus red seaweed was one of the first five species that researchers investigated to identify the compounds within extracts that caused strong effects against disease-causing cells. Anne Prusak, a former Georgia Tech student and research technician, separated the new molecules from other components of the extract by a process called chromatography, which takes advantage of the different chemical characteristics of compounds.
Finally, researchers used X-ray crystallography (work done at Emory University in Atlanta), nuclear magnetic resonance spectroscopy and mass spectral analyses to determine how carbon, oxygen, bromine and hydrogen atoms connected to make up the molecular structures of the 10 new natural products.
Much research is left to do before any of these compounds are used to formulate a drug available on the market, Kubanek said. It typically takes at least a decade from the discovery of a compound to the marketing of a new drug. If that does happen in this case, Fijian villagers and the Fijian government would benefit financially from the discovery because of an agreement that is already in place, she added. Because of the long timeframe in getting a drug to market, the project in Fiji provides other immediate conservation and economic development benefits to villagers and the government.