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January 27, 1997

American Cancer Society renews funding of research by UCSC chemist

By Robert Irion

Since mid-1993, researchers in the laboratory of UCSC chemist Joseph Konopelski have tried to construct an intriguing substance harbored within the tissues of a tropical marine animal. The substance may be a potent weapon in the fight against cancer. But there's a problem: Less than a thimbleful of the material exists, and no one can relocate the obscure animal from which it came.

Konopelski's proposal to make the substance from scratch drew the attention of the American Cancer Society, which granted $319,000 for the first three years of the project. Now, encouraged by the UCSC team's progress, the society has renewed its support with $200,000 for the next two years.

A portion of the new funding comes from a bequest of $1.6 million to the American Cancer Society's Santa Cruz County Unit from the estate of the late Col. Frank K. Schilling. Schilling's gift was in memory of his wife, Else H. ("Henny") Schilling, who died of breast cancer in 1985. He earmarked part of the bequest for cancer research conducted by institutions in Santa Cruz County.

The substance of interest to Konopelski, called "diazonamide A," was first described in 1991 by marine chemist William Fenical of the Scripps Institution of Oceanography. Fenical's team isolated the chemical from a soft-shelled animal, Diazona chinensis, that lived in a submarine cave off the coast of the Philippines. Tests showed that tiny amounts of the chemical killed colon-cancer cells in the lab. However, Fenical's divers haven't been able to find the animal again.

The best hope for further testing is for chemists to synthesize diazonamide A in the lab. Researchers managed that challenging feat recently with Taxol, a cancer drug derived from the bark of a rare yew tree in the Pacific Northwest. While diazonamide A is far from a proven drug, its structure is so striking that chemists think it holds much promise.

"This is just a fascinating molecule," says Konopelski, an associate professor of chemistry and biochemistry at UCSC. "The first time I saw the structure I knew it was something special. Nature wouldn't go to all this trouble unless it had something in mind. And this molecule is a lot of trouble, both for us and for nature."

Like many organic compounds, diazonamide A contains rings of carbon atoms bound to other elements, such as oxygen and nitrogen. Some parts of the molecule are fairly simple and have yielded to the techniques of Konopelski and his coworkers. However, other parts are uniquely demanding. For instance, two bulky atoms of chlorine sit virtually on top of each other, making it impossible for some of the carbon rings to rotate in space. Such rigidity, says Konopelski, is unusual in nature and tough to replicate in the lab.

The UCSC group has made the main parts of the molecule and now is trying to stitch them together. Team members published their progress in the July 1996 issue of the journal SYNLETT. Since then, they also have started to use computer models to gain a better understanding of how crucial parts of the structure move in space.

One indication of the molecule's allure is that unlike in 1993, Konopelski's team is no longer the only group tackling it. Indeed, some of the leading synthetic organic chemistry labs in the world now have diazonamide A in their sights. However, Konopelski is less interested in crossing the finish line first than he is in expanding the frontiers of his field.

"We take on these projects because we think there's good science in them," he says. "This is the most challenging project I've ever been associated with, and along the way we have defined some new chemistry." When the "race" to synthesize diazonamide A is over, Konopelski adds, research teams can focus on the vital task of determining what the compound does inside cells. They also can try to make subtle variations of the molecule that may combat disease more effectively than the original or with fewer side effects.

Key members of Konopelski's team include current graduate student Elizabeth Drotleff and former postdoctoral researcher Eduardo Veliz, now teaching at Kenyon College in Ohio. Partial support for the research was provided by the UC Cancer Research Coordinating Committee.

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