A photo finish for total taxol synthesis.

A photo finish for total taxol synthesis

Taxol - the complex anticancer compound derived from the bark of the Pacific yew tree, Taxus brevifolia- has finally yielded to the ingenuity of two chemistry research teams.

Both report that they've figured out how to make this drug in a laboratory without having to fell the precious evergreens.

Kyriacou C. Nicolaou, a chemist at the Scripps Research Institute in La Jo!la, Calif., and his colleagues reported the "total synthesis of taxol" in the Feb. 17 NATURE. Robert A. Holton, a chemist at Florida State University in Tallahassee, published his recipe for taxol in the Feb. 23 JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, based on results obtained in December 1993.

The two teams finished neck and neck after a 10-year race involving more than 30 research teams worldwide to make a test-tube version of this unusually intricate natural compound.

Identified in 1964 and analyzed structurally in 1971, taxol has revealed itself as a promising antitumor agent for ovarian, breast, lung, and skin (melanoma) cancers. Tests of taxol's safety for use by patients began in 1983. In 1992, the Food and Drug Administration approved it for treating ovarian cancer.

Yet the limited supply of natural taxol has hamstrung research and treatment efforts. In the early days of taxol research, all of the bark from a single 40|foot-tall, 100-year-old tree yielded one scant 300-milligram dose of the drug -- killing trees on a scale that made environmentalists apoplectic. The recent discovery of ways to extract taxol from European yew needles (Taxus baccata), a yew fungus (Taxomyces andreanae), and Taxus bushes have eased supply pressures.

Still, scientists must be able to synthesize taxol before they can make other, related antitumor agents. Taxol's unique structure - a diterpenoid compound with a core taxane ring, a rare four-membered oxetane ring, and an ester side chainpointed toward a previously unrecognized anticancer mechanism. Now chemists may tinker with the taxane ring and possibly improve it.

The two teams took somewhat different approaches to the synthesis. Nicolaou's group worked out a way to join two big chemical rings together, forging a third in the process. The chemical sequence involves more than 28 steps. Holton's group tried another tack. Since Taxol has two main components - a large, naturally extractable chunk, called baccatin III, hooked to a snowflake-like tail of 34 atoms - the Tallahassee chemists focused on the troublesome tail. They then figured out how to bind the two pieces together, curtailing a total synthesis that involves nearly 40 chemical steps.

But this whirlwind of work may bear future pharmacological fruit. Maybe chemists can tweak taxol into a more potent form with fewer side effects, diminishing patients' adverse sensitivity reactions. A drug that dissolves in water - taxol doesn't would ease treatment, too, as would a related drug to combat some tumors' resistance to taxol's cancer-fighting mechanisms.

Indeed, another generation of designer "taxoids" may, in the end, give rise to a preferred anticancer drug.