The anti-cancer drug Lankacidin C has been synthesized for the first time by a group of chemists at the University of Rochester. Details of the research are in today's issue of the Journal of the American Chemical Society.
For two decades its low toxicity has attracted scientists who have believed the drug could be particularly effective against such cancers as leukemia, melanoma, and lymphoma. But Lankacidin C is not used clinically as an anti-cancer drug because it's very unstable and is not quite potent enough, says Andrew Kende, Charles Frederick Houghton Professor of Chemistry and a member of the faculty of the University's Cancer Center.
Several companies in Japan and the U.S. have tried to enhance the drug, but none has been successful. Kende hopes his group's synthesis of the drug -- and the methods they've discovered in the process -- will spur new work which could make the drug a viable anti-cancer candidate.
"This drug is right at the border where it could have a good range of activity against a number of cancers," says Kende. "We're hoping the methods we've developed in synthesizing the parent compound will enable others to make more powerful derivatives."
Kevin Koch of Pfizer Central Research, who contributed to the research while he was a student at Rochester, agrees. "The synthesis is particularly valuable because it allows, for the first time, the preparation of a diverse array of Lankacidin analogs," he says. "This should speed the process of finding more potent compounds."
Lankacidin C is now used as an oral animal antibiotic in Japan and is effective against strep and staph infections. The drug has also shown some potential as an immunosuppressant, a property common to drugs used to prevent rejection in organ transplants.
The Lankacidin synthesis was extremely complex -- 34 separate steps beginning with just two basic building blocks, the sugar D-arabinose and L-aspartic acid. At each step along the way Kende's group had several possible chemical reactions from which to choose.
"You must put the reagents together in just the right way," says Kende. "It's like a chess game: You have to think far ahead to achieve the ultimate goal. You go for the target, but your approach can get killed at any step. You never know how a particular strategy will turn out."
While Kende guided the strategy ultimately used to synthesize the molecule, the six-year process was actually a string of successes by several excellent students, he says. Working with Kende on the project were Koch, former co-workers Istv n Kaldor and Gilbert Dorey, and current student Kun Liu, whom Kende credits with the final breakthrough enabling the group to finally make the molecule.
Kende is known internationally for synthesizing large, complex molecules from simple starting materials, and holds more than three dozen patents for his drug syntheses.
"This is an elegant synthesis of a rather sensitive, structurally unique natural product accomplished in the typically ingenious Kende fashion," says Koch. "The key to Kende's continued success is his ability to identify the most challenging structural feature of the target molecule, then design a synthetic strategy to overcome the obstacle."
Kende was one of the first to synthesize Camptothecin, an anti-cancer drug which was left for dead more than a decade ago but, with some recent changes, has become hot at several pharmaceutical companies. "It's common to have a drug that doesn't quite make it at first, to be resurrected in a different, more powerful form several years later," says Kende. "You never know which ones are going to pan out."
This project was funded by the National Cancer Institute, the French Ministry of Foreign Affairs and l'Institut de Recherches Servier, and by the Sherman Clarke Fellowship program. tr