Amphidinolides, a family of natural compounds that have shown promise as powerful antitumor agents, pose problems for cancer researchers because they are found in only minute amounts, and only in microscopic marine flatworms that live off the coasts of Japan and the U.S. Virgin Islands. Nature keeps a tight lock on its supply of amphidinolide.
Work by University of Illinois at Chicago chemistry professor Arun Ghosh may solve this problem. He's successfully developed a way to synthesize amphidinolides, making potentially abundant quantities available for cancer research. Ghosh and doctoral student Chunfeng Liu reported on their technique in the Feb. 6 online edition of the Journal of the American Chemical Society.
"We wanted to synthesize amphidinolide in the laboratory for subsequent biological studies," said Ghosh. As an antitumor agent, "nobody knows its exact mechanism of action. It could be a microtubule stabilizing agent, like Taxol, or it could cause cellular apopotosis, where cancer cells are killed by chemotherapeutic agents," he said.
Ghosh and Liu began their work in January 2002 and by November, successfully synthesized a highly potent member of this family of compounds, designated amphidinolide T1. They've produced about 8 milligrams of the compound in their UIC laboratory and have sent a sample to the National Cancer Institute in Frederick, Md. for testing by Ernest Hamel, a noted expert in cancer research.
While Hamel said he has not yet tested the amphidinolide sample, he added, "its synthesis, of course, is a tour-de-force independent of its biological activity."
Nuclear magnetic resonance spectroscopy and other sophisticated technologies helped establish the chemical structure of many natural amphidinolides. Ghosh used that structural information and applied a technique called retrosynthetic analysis, developed by his post-doctoral mentor, Nobel laureate Elias James Corey, of Harvard University.
"On paper, we break the molecular structure down to its most basic parts, then we design chemical schemes to rebuild it in the laboratory," said Ghosh. "It's a very complex molecule. Synthesis of a molecule of this nature is an art, and it becomes a challenge of how to put it together in the most elegant way."
Using planned synthetic strategy as a guide, the step-by-step construction of the molecule in the laboratory flask presents enormous challenges. It's like trying to solve a complex puzzle. "In the end, this synthesis not only gives you a final product," said Ghosh, "it also allows you to discover a lot of important and useful reactions along the way."
An earlier synthetic success of Ghosh's, the compound laulimalide, is showing promising results in laboratory tests against certain cancers previously treated by the drug Taxol, and has shown the ability to kill cells resistant to Taxol. The UIC chemistry professor hopes amphidinolide will prove to be even more effective as an antitumor agent.
"We hope we can modify the molecule to make it even more potent and more selective," said Ghosh. "Nature has given us only one molecule, but once we've synthesized it in the laboratory, we have the potential to make hundreds of thousands of different variations."
"When you look at all the good drugs available, you find about 60 to 70 percent are derived from nature. In the past, molecules like amphidinolides could not be discovered because we didn't have the technology. Now the power of chemical design and synthesis provides a new tool for drug discovery."
The National Institutes of Health provided funding for Ghosh's research. He hopes to win additional grants to do in-depth biological studies and begin synthesis of an even more potent member of the amphidinolide family, called amphidinolide N.
"That's our next target, and we're up to the challenge," said Ghosh. "The work on amphidinolide T1 was just the beginning. A lot of the story has yet to unfold."
Paul Francuch, (312) 996-3457, firstname.lastname@example.org