April 14, 1997

Chemists squeeze potpourri of active compounds from marine sponges

Earth's natural pharmacy is stocked with medicines derived from microbes, plants, and other denizens of the land. The ocean's waves may conceal an equally rich supply of potential drugs, some chemists believe. Although marine organisms haven't yet yielded an approved drug, promising compounds continue to surface--including an intriguing new toxin from a grape-sized sponge found in Papua New Guinea.

Chemist Phillip Crews and his team at UCSC collected the purplish-green sponge, Psammocinia, in 1993. The sponge's major metabolic products didn't display notable toxic activity against cells. However, graduate student William Clark persevered. Clark separated the sponge's minor constituents with a bioassay-guided isolation that probes for toxicity to brine shrimp. These shrimp, the National Cancer Institute has found, are sensitive to compounds that also kill cancer cells. After many purifications, Clark isolated an especially potent product, called "cyclocinamide A."

Cyclocinamide A packs some chemical surprises, Clark discovered. The molecule is a "hexapeptide" of six amino acids, including one complex with chlorine that chemists have never seen in a marine product. Indeed, Clark suspects that cyclocinamide A comes not from the sponge, but from symbiotic cyanobacteria that colonize the sponge like low-rent houseguests.

Biologists Thomas Corbett and Frederick Valeriote of Wayne State University worked with the Crews group to test cyclocinamide A against cancer cell lines. Their promising results, combined with the brine-shrimp assay, convinced the researchers that the compound deserves in vivo testing in living animals. However, such testing requires 100 milligrams of material. Cyclocinamide A was such a minor ingredient that Clark only isolated about 6.7 milligrams--roughly 0.5 milligrams of which remain. Further, UCSC divers haven't yet found large numbers of the same sponge again in Papua New Guinea's reefs.

So, chemist Paul Grieco of Indiana University is working on synthesizing the molecule in his lab. If he succeeds, the in vivo testing could proceed with a manufactured substance identical to the one found in the sea.

Clark, who will earn his Ph.D. in June, emphasizes that cyclocinamide A--and all marine natural products--face steep odds against reaching the pharmacy shelf. For him, the main lesson is that diving deeply into the chemistry of each new marine organism may bring up hidden treasures.

"This was a minor constituent, and it was very hard to isolate," he said. "We probably will find new and interesting compounds if we look hard enough, even in sponges studied 10 or 15 years ago. Mother Nature isn't going to give away all of her secrets at once."

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