A publication for the faculty, staff, administrators, and friends of California State University, Chico
October 13, 2005 Volume 36 / Number 2


Cutting-Edge Research in Constructing Therapeutic Agents for Cancer Treatment

David Ball, Department of Chemistry, received his PhD from UC Santa Barbara and joined the Chico faculty in 1974. Every summer for almost 25 years, Ball left Chico for universities that had the analytical instruments he needed to carry on his research in synthetic organic chemistry. In 1998, he took a sabbatical and returned to UC Santa Barbara, where he learned techniques that he has applied since then in his research in the synthesis of retinoids, a class of organic molecules that are natural and synthetic analogues (related to parent compound) of Vitamin A.

In 1999, Ball and the Department of Chemistry were awarded a National Science Foundation grant for a $215,000 high-field superconducting nuclear magnetic resonance spectrometer. It allows researchers to elucidate the structures of the compounds they make.

Ball and his students continue to collaborate with Bruce H. Lipshutz and other chemists from UC Santa Barbara in the synthesis of biologically active compounds, specifically retinoids. The research involves using organometallic reagents (chemicals used in a reaction) to efficiently construct these physiologically active compounds. The group recently published an article that presents the successful use of this cross-coupling methodology in the synthesis of several new retinoid analogues.

Retinoids have been used for some time for the treatment of acne, in the prescription drug Accutane, for example. Currently used in experimental treatments of various kinds of cancer, retinoids have been approved for some lymphomas and for use with some childhood cancers.

Jennifer Howell, a student researcher, wrote in a research paper on the project, “The retinoid attack mechanism on cancer cells is different from conventional therapeutic agents that act by poisoning. Retinoids act by retarding the proliferation of immature embryonic cancer cells and promoting maturation by differentiation. This process leads to programmed cell death.”

Prolonged use of naturally occurring retinoids produces toxic side effects, but synthetic retinoid analogues have demonstrated similar lethal actions toward cancer cells with few side effects.

The task of Ball and his co-researchers has been to create more versatile and efficient processes to synthesize these potential retinoid receptor antagonists. The methodology of this research centers on creating new carbon-carbon bonds by connecting carbons in a stereospecific manner, that is, producing a desired three-dimensional orientation of the groups being connected.

“Getting the stereochemistry right is what nature does extremely well and efficiently; imitating nature is very difficult to do in the laboratory,” Ball said. “If it is not right, then the molecule doesn’t get to where it needs to go, which, in the case of these retinoids, is to the nucleus of the cancer cell.”

Ball and his colleagues have been creating new molecules that can be used by biologists in actual cancer treatment trials. The research group has essentially accomplished what it set out to do, said Ball, which is to come up with a method so that anyone can make a large set of molecules for testing. “We supply the synthetic scheme to the chemistry community such that these potentially physiologically active molecules can be easily assembled and evaluated for efficacy in cancer treatment,” said Ball.

Ball received a Professional Achievement Honor in 2005 for his research and for his mentoring of undergraduate students. He has obtained more than $50,000 from pharmaceutical companies for student summer research money. He and colleagues recently submitted an NSF grant proposal for Research Experience for Undergraduates, which provides funding for summer stipends for students.

What is next for Ball? Continuing research in developing a synthetic scheme to produce a molecule that is found in the colons of about 7 percent of people who eat a Western diet. This highly mutagenic compound, fecapentaene, used to be thought to be a precursor of colon cancer, but is now thought to be involved in cancer prevention, perhaps as a free-radical scavenger. Using a similar synthetic approach to that used in the retinoid analogue research, he and his student co-workers are attempting to stereo- specifically construct this compound.

—Kathleen McPartland