Radspieler, Alexander: Untersuchungen zur Synthese von Diazonamid A und Phorbazol A und C


Kapitel 12. Anhang

Am 31. Januar 1997 erschien im San Francisco Chronicle ein populär-wissenschaftlicher Artikel von Charles Petit, der sich mit der Isolierung und potentiellen Bedeutung von Diazonamid A beschäftigt. 130 Obwohl einige Sachverhalte stark vereinfacht dargestellt sind, ist dieser Bericht nachfolgend zitiert, um zeigen, wie diese Substanzklasse außerhalb von Fachpubllikationen ihren Niederschlag gefunden hat.

Patch in the Pacific Holds Hard-to-Find Medicinal Marvel

Somewhere stuck to rocks in the western Pacific Ocean are strange sea creatures like blobs of stiff jelly, their tissues rich in a chemical unlike anything known to science - a substance that has killed colon cancer cells in laboratory tests.

Unfortunately, the people who found them cannot find any more.

The frustrating story starts with William Fenical, a chemist at the Scripps Institution of Oceanography in San Diego. He led an expedition in 1991 to the Philippines, prospecting for marine creatures that might produce medically useful compounds. In a cavern 100 feet under the sea near the remote island of Siquijor, he and other researchers scraped about two pounds of living material from a rock.

Testing extracts of the tissues of this cave-dwelling invertebrate, they isolated from its tissues a bizarre chemical that kills colon cancer cells.

It was a perfect setup for further study, with eventual testing in animals and then people --if its initial promise holds. But the thimbleful of the mystery substance has long since been used up.

A subsequent expedition could find no trace of the sea creatures, said Fenical. "Obviously, there are more of them out there. Chances are, it is abundant in many places. The question is, where? If you don't see it where you saw it before, it becomes like the needle in a haystack. The ocean is so vast."

To him, the episode illustrates both the potential payoffs of chemicals produced in the sea and the challenge of finding them.

Now, the main hope for studying the intriguing compound comes from a laboratory at


the University of California at Santa Cruz, where chemists using a blueprint of its structure are trying to make it artificially.


Even if it does not cure cancer, the material is impossible to resist, said Santa Cruz organic chemist Joseph Konopelski. "This is the most challenging problem I have even been associated with as a professional chemist -- 13 years here as a professor, and before that as a graduate student."

Only further testing can demonstrate whether the compound, called diazonomide A, will be useful medically. But already, Konopelski said, it is clearly very odd. Standard chemical rules suggest that it should not even exist. When Konopelski tries to put together a model of it using plastic balls and other shapes to represent atoms, it won't work. "The pieces don't fit, you have to jam them in," he said.

And the resulting molecule is so rigid that it may have unique biological properties. Most proteins, enzymes and other organic molecules can bend easily. "This thing is like a board," he said.

The molecule consists of 99 atoms, including 40 carbons, 45 hydrogens, six nitrogens, six oxygens, and most important, two chlorines. The chlorines are shoved unnaturally closely together, pinned by rings of carbon. They stiffen the whole structure.

So far, Konopelski and two graduate students have synthesized about six components of the molecule, and they think they may be able to assemble them into a duplicate of the original in a year or so. Then, if they can make enough of it, medical testing can continue. The American Cancer Society has paid more than $500,000 to back the effort.

And Fenical expects to resume the search for the animal, which has been seen before and has the scientific name Diazona chinensis.


Although its adult form is stuck to a rock like a plant, it is an animal. It is an ascidian, a member of a group of animals called tunicates that includes things like sea squirts -- resembling anemones. The creatures live in colonies, embedded in a tough, semitransparent tissue. The single colony found in 1991 resembled a translucent cow pie, about six inches across and two inches thick.

"It's kind of pretty when you look at it close up," Fenical said. "You can see the little animals inside. They are slightly orange tinted, all lined up in rows. Because such animals


seem so vulnerable to predators," he said, "they often depend on chemical defenses that make them poisonous to other creatures -- and which often offer novel medical properties."

After discovering the potential anti-cancer properties in the animals' tissues in laboratory tests, Fenical and colleagues at Cornell University bombarded the material with X-rays and subjected it to other tests to determine its molecular structure.

Konopelski at Santa Cruz said that trying to make the chemical "is not like building a television or something, where you know how to put it together. It is more like climbing a mountain for the first time. You plan your route, but when you actually start up, you find yourself going up blind chutes and have to turn around and try something different."

In the end, synthesizing the compound may be the scientists' only choice if further tests show that it has medical value. Although the creatures, if found, would be a boon to initial testing, Fenical said harvesting them would not yield enough of the material for widespread medical use.

©1999 San Francisco Chronicle

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