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Pine trees to the rescue since there's not enough taxol from yews
STANFORD --In the key to their progress toward synthesizing the drug taxol in the laboratory, Stanford University chemists have found a starting material not quite "as cheap as dirt," but "almost as inexpensive as potting soil."
They described their findings today in a press conference on a variety of approaches to taxol synthesis, organized by the American Chemical Society (ACS) during its national meeting in San Francisco. The research will be outlined in full at an ACS symposium on taxol Wednesday, April 8.
Taxol is a promising anti-cancer drug that so far can be obtained only through extraction of the bark of the slow-growing Pacific yew tree, taxus brevifolia. The drug has shown remarkable promise in clinical trials as a treatment for ovarian and breast cancer, but it is in short supply.
Prof. Paul Wender reported that by building on pinene, a molecule found in pine trees, he and his group have developed a shortcut method of making the three-ring taxol core molecule. They are close to completing its final functionalization - if their work goes according to plan, they expect to achieve a total synthesis by the end of 1992.
Pinene has many attractive attributes as a starting material for building taxol in the laboratory. It is one of the most widely available natural products and a major component in such industrial solvents as turpentine.
"There's an aesthetic beauty and certainly a practical consequence to the fact that the precursor in the synthesis of a material that is difficult to get from one tree is one of the most abundant materials in another tree," Wender said.
"You can buy big containers of this; you can buy railroad-car- size quantities of pinene and it is inexpensive."
It is also important that the chemical structure of pinene has the same "handedness" as the taxol molecule, a feature that is crucial to developing a synthetic source of taxol with the same powerful anti-cancer effect. In addition, pinene, a monoterpene, contains 10 of the carbons that are required in the 20-carbon skeleton of taxol, a diterpene.
"So, half the solution to taxol we buy," Wender said, "and we need to add to that only the remaining 10 carbons." As a result, their method is probably one of the shortest discovered to date for developing a synthesis of taxol.
So far, by building on pinene, the Stanford group has assembled the three rings of the core molecule of taxol and has put together all of the key functional groups on the first two of these three rings. They are working to complete functionalization of the third ring.
"If all goes well, we hope to finish a first generation synthesis of that tricyclic core this year," Wender said.
To complete the synthesis of taxol, the core, a natural product called baccatin, or a closely related compound, would have to be attached to a side chain. Other researchers already have been able to attach the side chain to natural baccatin, so this last step appears to be a relatively small hurdle, Wender said.
"However, even at the stage of attaching the side chain to the core molecule, we will not have reached a process that will allow us to fill bottles with taxol," Wender emphasized. "That would be the next goal."
Current estimates are that hundreds of kilograms of taxol per year will be needed.
Wender noted that many laboratories are working on technologically different approaches to producing taxol, including plant tissue culture, biosynthetic approaches, plant genetic approaches and botanical approaches. He expects that chemical synthesis will figure significantly in any solution and that reports of a total synthesis may occur before the end of the year from several of the groups that are working hard on this problem.
Ultimately, however, synthesizing taxol will not be sufficient to solve the problems of short supply.
"Claiming a synthesis is going to be different from claiming a practical synthesis," Wender said. "And that will be related to the cost of materials and the number of steps required.
"That's why we're excited about pinene. It is a starting material that we estimate might cost on the order of pennies per gram."
He said the approach to a taxol synthesis based on pinene grew out of discussions with graduate student Tom Mucciaro in late 1988 and early 1989.
"It was apparent from clinical trials at that time that taxol was potentially significant for treatment of human cancer, creating a greater urgency for its economic production," Wender said.
"With that in mind, we committed ourselves to three goals: to come up with a practical synthesis for taxol; to understand how the drug works by making analogs of it; and to use this knowledge to design new and improved second-generation drugs."
Wender said the researchers want to know exactly how taxol works to find out whether its anti-cancer properties could be produced by a less complex variation, rather than the whole taxol molecule.
The group is optimistic that simpler versions of taxol may be equally effective for treating cancer.
"Taxol is produced by a tree, one could argue, for purposes other than curing cancer in humans," Wender said. "All of the functional groups on taxol might be required for its activity in the tree, but some might not be required for its role as an active anti-cancer agent.
"We've already accomplished an important goal, and that is being able to make, in a practical fashion, analogs that have many of the features of the taxol molecule. We've been able to attach the side chain to these analogs; and we're now doing work to see whether they are active, and ultimately what features are required."
Based on an understanding of what makes taxol successful, the group hopes to design and synthesize second-generation drugs.
"The difference between the second generation and the first generation would be hopefully that we can make compounds that are more potent, easier to formulate compounds with none of the side effects associated with taxol," Wender said.
Wender attributes his group's progress to the dedication and around-the-clock work of the graduate students and postdoctoral fellows in his laboratory. They include postdocs Michael Natchus, Takeshi Ohkuma, Bernd Peschke, Tony Shuker, Katsuhiko Tomooka and Ludger Wessjohann; and graduate students Paul Floreancig, Tim Glass, Daesung Lee, Tom Mucciaro, David Rawlins and James Sutton.
Their research is funded by the National Institutes of Health and by Bristol-Myers Squibb Co., which has the exclusive rights to develop taxol in the United States.
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