Synthetic path to new transplant drugs.

Scientists have finally succeeded in synthesizing rapamycin, a complex chemical first isolated 20 years ago from a soil fungus found on Easter Island. In recent years, researchers have eyed the substance's potential as a drug that would suppress the body's urge to reject a transplanted organ or tissue. The ability to make the molecule using the techniques of organic chemistry -- organisms -- may usher in a new class of immunosuppressant drugs, writes a group of chemists in the May 19 JOURNAL OF THE AMERICAN CHEMICAL SOCIETY.

Over the past decade, transplant success rates have risen, thanks largely to cyclosporin, another immunosuppressant drug obtained from a fungus. Cyclosporin, however, can cause serious side effects, such as hypertension and kidney and liver damage, so scientists have been eager to find an alternative. Researchers at the pharmaceutical company Wyeth-Ayerst in Princeton, N.J., have begun clinical trials of rapamycin. At present, they produce the drug by fermentation, a process that involves culturing large batches of the fungus.

The new synthesis technique will not replace the current production method, but it will enable scientists to develop chemical relatives of rapamycin, says K.C. Nicolaou, leader of a research team at the University of California, San Diego, and the Scripps Research Institute in La Jolla, Calif. Indeed, he and his colleagues are now aiming to make improved versions of rapamycin that will resist quick degradation in the body.

To synthesize rapamycin -- a 31-carbon ring structure -- the scientists first constructed an open chain of 29 carbons. The chain had the same variety and placement of highly sensitive side groups as rapamycin. They then closed the ring using a process called "stitching cyclization," in which a two-carbon fragment containing reactive tin groups forms a bridge between the ends of the chain. The group obtained a "modest" yield of 28 percent, "quite satisfying" considering the molecule's complexity, says Nicolaou.

New versions of rapamycin with different side groups will help scientists probe the mechanisms of immunosuppression, says Nicolaou. "We're hoping to use the analogs that we create with this chemistry to increase our knowledge about how these kinds of drugs interact with the immune system," he says.