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Promising New Anticancer Drugs from Rare Corals Synthesized in the Laboratory

La Jolla, CA. November 19, 1997 -- Scientists at The Scripps Research Institute (TSRI) have performed the first total chemical synthesis of a number of promising new anticancer compounds, first isolated from rare species of corals and related marine organisms. The team, headed by K.C. Nicolaou, Ph.D., succeeded in assembling these compounds in the laboratory by designing a multistep strategy using simple chemical building blocks such as carvone, an oil readily available from caraway or dill seeds, frequently used as a commodity chemical in perfumes and foods. The scientists hope to produce synthetic analogs for biological screening purposes that could ultimately lead to more effective and safer therapeutic agents than the original compounds.

According to Nicolaou, Chairman of the Department of Chemistry, Skaggs Professor of Chemical Biology, and Darlene Shiley Professor at TSRI, and Professor of Chemistry at UCSD, "There is always risk of failure associated with any drug discovery and development program. What we can say for certain at these early stages of the research is that the new substances look very promising in killing cancer cells and now we know how to make and fine-tune them in the laboratory for further biological investigations." The drug discovery and development process often takes more than 10 years and the cost for development frequently reaches several hundred million dollars.

Eleutherobin, one of the novel compounds synthesized, appears similar to the anticancer drug, Taxol® in its mechanism of preventing cells from dividing. It originally was found by W. Fenical and his co-workers at the Scripps Institution of Oceanography, in soft corrals collected from a region of the Indian Ocean near Australia, known as Bennett's Shoal. The specific species of coral from which eleutherobin was isolated is very rare and has not yet been fully identified, except that it belongs to a family known as eleutherobia. The compound has shown powerful properties against cancer cells.

Fenical commented, "The stuff was so extraordinarily potent that it was dangerous to handle. You could dilute it a million-fold, and it still killed cells very powerfully."

The second group of substances, sarcodictyins, were first discovered from a Mediterranean stoloniferan coral (sarcodictyon roseum) species in 1987 by an Italian research group led by F. Pietra, but its anticancer activity was only recently reported. The natural scarcity of these compounds coupled with their promising anticancer properties prompted a search for their laboratory production. These chemical syntheses address the issue of supply and open the way for further pharmacological investigations, which may lead to the development of these new substances as chemotherapeutic agents against cancer. Applying their newly developed synthetic methods, the scientists already have embarked on a program directed at the generation of libraries of these compounds employing sophisticated combinatorial chemistry techniques.

Scientists have determined that eleutherobin's unusual method of blocking cell division is similar to that of taxol. Nearly all cells have a complex structure within them called the cytoskeleton, an intricate scaffolding of minute fibers called microtubules. The scaffolding changes according to the functional state of the cell, appearing and disappearing as the microtubules break down and then reassemble. While a number of compounds, including some anticancer agents, can inhibit this reassembly thereby preventing cell division, eleutherobin and taxol have the opposite effect. Rather than breaking down the internal structure of cells, these compounds paralyze them, making them so stable as to prevent movement, replication or cell division.

The total synthesis of taxol was achieved by the Nicolaou group in 1994. Taxol® has been called a breakthrough treatment for breast and ovarian cancers. In addition, another group of potential anticancer agents known as epothilones have been isolated from a species of bacteria found in soil samples collected from the banks of the Zambesi River in the Republic of South Africa, and recently synthesized by Nicolaou and colleagues. The epothilones currently are under development by a number of pharmaceutical companies.

The team that successfully synthesized eleutherobin included postdoctoral fellows Drs. Jinyou Xu, Floris van Delft, Takashi Ohshima, Sanghee Kim, Seijiro Hosokawa, and Dionisios Vourloumis, research associate Tianhu Li, and graduate student Jeff Pfefferkorn. The work was supported by The Skaggs Institute for Research, National Institutes of Health, Novartis, and CaPCURE.

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