AMERICAN researchers isolated a "chemical weapon" from Pacific yew tree bark 20 years ago. The chemical, Taxol, kills the tree's pests by halting normal cell division. This intriguing property led to the idea that Taxol might become a weapon against runaway cell division in cancer.
Clinical trials on Taxol began in 1983 on women with ovarian cancer, which is often resistant to conventional anti-cancer drugs. The trial's success was apparent by 1988, and further encouragingresults on breast cancer have lead to a huge demand from researchers. However the Pacific yew produces only a limited quantity of Taxol, so alternative sources are needed.
Felling trees is fortunately not the only way researchers can get hold of the chemical.Ever since scientists saw its potential, organic chemists have been wrestlingwith Taxol's complex structure to find ways of making it in the laboratory.
A chemical jigsaw is now being pieced together by chemists. Bristol Myers Squibb, the
pharmaceutical company, recently announced that it intends to start producing Taxol next year using a compound known as 10-deactylbaccitin III (10 -DAB III).
This is a chemical relative of Taxol found in yew needles and twigs, so should
provide a renewable, sustainable source of starting material. BMS will base production on a so-called semi-synthetic process, discovered by Robert Holton of Florida State University, which starts with 10-DAB III and uses a few chemical steps to reach Taxol.
According to Holton, Taxol's complexity would preclude the commercial viability of a "total" synthesis within the next five to seven years. By that time, he says, "some Taxol mimic will have been found."
However, some researchers, such as Kyriacos Nicolaou and his colleagues at the Scripps Research Institute and the University of California, are quickly approaching such a total synthesis. Although transforming 10-DAB III takes only a few steps, it is expensive and complex. A total synthesis would use the simplest of compounds. In the Journal of the Chemical Society, Nicolaou's team reports having discovered an important entry to the two main pieces of the Taxol jigsaw, which could produce such a process.Nicolaou emphasises that theirs is not a complete solution to the puzzle, but by merely aiming for Taxol, he and his colleagues hope to hit some "biological mimics" along the way.
Nicolaou believes that a Taxol mimic "might be even better than Taxol itself". By a process of "going back and forth between chemistry and biology we should be able to find a more effective drug". In this way they could learn which parts of Taxol's structure endow it with anti-cancer activity."Only a fragment of the molecule might be necessary," he says, which would almost override the need for a total synthesis.
Nicolaou adds: "Taxol, with all its glory, is not the perfect anti-cancer drug." It has a number of disadvantages such as lack of solubility in water, which reduces absorption from the gut and necessitates premedicative "carrier" drugs.
It is likely, however, that a total synthesis will require a huge number of reaction steps. Nicholas Lawrence, who heads a research team at UMIST studying Taxol, believes: "Twenty-five steps would cause problems in a research laboratory, let alone on a production scale," though "the payback for success will be enormous."
BMS's investment in Taxol (estimated at $150 million by the end of the year) involves significant risk as they have only five years' exclusivity on the drug. In that time other companies may find a Taxol mimic, such as Rh├┤ne-Poulenc Rorer's Taxotere, to be more effective; or an efficient total synthesis might be found.
