May 4, 2001 COLUMBUS, Ohio - Using a frothy brew of soil bacteria as a guide, chemists at Ohio State University have synthesized a substance that may lead to a new generation of chemotherapy drugs.
Laboratories around the world have struggled to create a synthetic version of the chemical, called azinomycin A, ever since it was discovered in bacteria in 1986. The natural form of the chemical breaks down too quickly for scientists to test whether it could be used to combat cancer cells in the body.
Now that Ohio State researchers have completed their quest to build an exact copy of azinomycin A atom by atom, they can try to redesign the chemical into a stable, medically usable form, said Rob Coleman, professor of chemistry at Ohio State and principal investigator of the project.
This research, which was funded by the National Cancer Institute, appears in the current issue of the German chemistry journal Angewandte Chemie. The journal issue, dated May 5, 2001, is set to appear on the World Wide Web at on May 2, 2001, at http://www.angewandte.com.
"More important than synthesizing the agent is what we've learned along the way," Coleman said. "We need to understand the chemical mechanisms behind azinomycin A so that we can develop more effective anti-tumor agents in the future."
Coleman said an enhanced version of azinomycin A might make an especially potent chemotherapy agent. He pointed to laboratory tests from 1987, when Japanese scientists found that the short-lived natural version of the chemical attacked tumor cells in a test tube and was effective as combating cancer in animal models.
Scientists now believe azinomycin A and its sibling azinomycin B -- both produced by a type of Streptomyces soil bacteria - attack DNA by forming very strong bonds, and are two of only a handful of chemicals that bond to DNA in this way.
In 1989, Coleman first began to design the chemical steps needed to synthesize azinomycin A and B in the laboratory. He started the work at the University of South Carolina and, beginning in 1996, at Ohio State.
Over that time, several researchers contributed to the project. In particular, Coleman credits Andrew Carpenter and Thomas Richardson, both his former Ph.D. students, and Jian-She Kong, an Ohio State postdoctoral researcher in chemistry, with performing important preliminary studies. The Ohio State work in the Angewandte Chemie paper was done by Coleman's co-authors, Jing Li and Antonio Navarro, both postdoctoral researchers.
Coleman and his colleagues devised a strategy for breaking the complex-shaped azinomycin A molecule into five smaller pieces. Over 11 years, the researchers performed essentially all possible series of chemical reactions these constituents could undergo, starting over whenever they reached a chemical dead end.
The researchers charted each chemical reaction like a composer would write a score for a symphony orchestra, Coleman said: "We had to write every note for every instrument, think about how the different instruments would play off each other."
To obtain natural azinomycin A for comparison, they fermented a broth of Streptomyces bacteria, which Coleman says resembles a good Irish ale, and isolated both of the azinomycins.
In February 2001, the researchers obtained the synthetic form of azinomycin A that perfectly matched the original. "For all intents and purposes, they are absolutely indistinguishable," Coleman said.
Now the Ohio State researchers are investigating how azinomycin A and B form such strong bonds with DNA. They have also started tinkering with the synthetic formula.
"We think we're beginning to see why the natural form is unstable, and that gives us some idea of where to go next with building new anti-tumor agents," Coleman said.
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