Beyond Pharmaceuticals: Business And Academic Leaders Forecast The Future Of "Combinatorial Chemistry"

October 14, 1998

NEWARK, DEL. -- Over the past decade, combinatorial chemistry--a technique for rapidly creating and testing vast `libraries' of chemical compounds--has emerged as a key strategy for drug discovery. Leaders in the combinatorial field, however, recognize that its potential applications extend far beyond pharmaceuticals.

At a University of Delaware conference, 15 industry and academic experts Oct. 22-23 will describe how combinatorial chemistry also is speeding the search for novel catalysts, specialty chemicals and a wide range of new materials.

Someday, combinatorial processes may even help scientists grapple with such complex problems as speech recognition, says honorary conference chairperson H. Mario Geysen, a Distinguished Research Scientist with Glaxo Wellcome Inc. and the inventor of combinatorial chemistry. The field might support investigations of, say, room-temperature superconductors, or the likelihood that life exists elsewhere in the universe, Geysen says.

Along with Geysen, top scientists from Symyx Technologies, ArQule, DuPont and other industry leaders will present their views of this swiftly developing field to over 200 attendees at UD's Newark, Del., campus.

"After only 10 years, combinatorial chemistry is completely accepted and fully integrated into pharmaceutical companies," says W. Henry Weinberg, chief technical officer at Symyx Technologies of Santa Clara, Calif., a company that develops and applies combinatorial methods for the chemical and electronics industries. Within the next three years, Weinberg continues, it appears that combinatorial methods will yield even more important, far-reaching results when applied to discovering and improving non-drug materials such as polymers and catalysts. "This is the first conference devoted entirely to this emerging technology," he adds.

Weinberg--who also is a professor of chemistry, chemical and materials engineering at the University of California in Santa Barbara--will provide an overview of the emerging field of combinatorial materials science. To illustrate its remarkable promise, he will describe efforts to identify and refine a variety of luminescent materials and catalysts-compounds that increase the efficiency of chemical reactions.

Polymers, Peptides And Patches

Other speakers, including Paul J. Fagan of DuPont and Amir Hoveyda of Boston College, will provide detailed accounts of combinatorial approaches to catalysis. Symyx's director of catalyst research, Howard W. Turner, will highlight the synthesis and screening of catalysts intended for use in manufacturing a variety of valuable polymers. These catalysts could solve what he calls "some of the greatest challenges in material science today."

Combinatorial chemistry has proven a powerful tool in the hands of researchers, Turner says, enabling them to develop compounds to meet specific needs, despite the lack of initial clues as to what types of chemicals would do the job.

Not only have combinatorial methods yielded powerful catalysts for polymer production, but they also have yielded the means to design new polymers to heal damaged tissues and pinpoint the delivery of fragile peptide drugs. And, in the near future, combinatorial methods may lead to improvements of transdermal drug "patches," currently used for delivering nicotine and other substances through the user's skin.

Joachim Kohn, a professor of chemistry at Rutgers University, will describe the creation of a "library" of novel biomaterials based on widely used polymers called polyarylates (found, among other places, in liquid crystal watch displays).

Hundreds Of "Lottery Tickets"

Because scientists cannot yet predict which chemical structures will, for example, help drugs in transdermal systems penetrate the skin, scientists are "reduced to trial and error," Kohn says. "It's like playing the lottery: if you make and test one compound at a time, it's like buying a single ticket," he explains. "But combinatorial methods allow you to make hundreds of compounds and test them rapidly, so you greatly improve your odds of picking a winner."

From 112 polyarylate compounds in his library, Kohn has already found several promising leads. These include polymers that appear to promote cell growth, migration and attachment: critical processes for tissue replacement. In addition to helping Kohn beat the odds of finding such molecules, studying the compounds in his library may allow him to identify structure-function relationships that would enable him to design-rather than simply screen for-improved biomaterials.

Introducing "Click Chemistry"

Another speaker, K. Barry Sharpless of the Scripps Research Institute, studies the synthetic methods used to create combinatorial libraries, as well as to manufacture the promising compounds they yield. With a technique he calls "Click Chemistry," Sharpless says he hopes to greatly increase the rate by which new compounds can be made. Click Chemistry involves assembling compounds in a single step-rather than a series of reactions-from several reactive components that "click" together easily. "We're looking for unknown, easy-to-make structures that act in new ways," he states.

"This is not conventional combinatorial chemistry," Sharpless adds. "We want to make drugs and other useful materials from much simpler building blocks [than are currently used]." Nature, he says, teaches us that the most efficient way to build molecules is by assembling them from smaller molecules that already contain carbon-carbon bonds, rather than by making new bonds between carbons. Click Chemistry reactions generate so-called heteroatom bonds between carbon atoms and non-carbon atoms such as nitrogen or oxygen--bonds that are much easier to make than those between carbons.

Chemicals called olefins, which are easily derived from crude oil and natural plant oils, provide a cheap source of building blocks for Click Chemistry, Sharpless says. Simple reactions create "sticky spots" on olefins, which allow them to be "stitched" together with a single heteroatom. From these basic ingredients, Sharpless hopes to build new catalysts, polymers and-especially-medicines, including drugs that even the world's poorest people could afford.

A Powerful Problem-Solving Tool

Indeed, Glaxo Wellcome's H. Mario Geysen contemplates applying its methods to solve a wide variety of problems--including some, such as speech recognition, that have very little to do with chemistry. Geysen, Distinguished Research Scientist with Glaxo Wellcome Inc., first used a combinatorial method to identify the chemical group on an antigen that was recognized by a specific antibody. They succeeded in this task by constructing and screening a set of 1.28 billion peptides, out of which they found a handful that bound tightly to the antibody.

Now, however, Geysen is using a combinatorial strategy to determine the best possible way to perform a single chemical reaction: by testing all possible combinations of solvents, temperature, catalysts to reveal the most efficient way to combine certain reactants. By using combinatorial methods, he says, he and his coworkers were able to perform 150,000 permutations of a chemical reaction within a week.

"Most combinatorial chemistry is focused on producing compounds, but I use it as a general way to solve difficult problems," Geysen observes. Fundamentally, he explains, combinatorial processes are designed to provide maximum information--and thus, a likely answer--to complex questions. These could include a better understanding of speech recognition, techniques for creating a room-temperature superconductor, or a strategy for analyzing the possibility of life elsewhere in the universe. "Combinatorial chemistry's greatest achievement," he says, "is that it has showed us that we can deal with very large problems by thinking about them in unconventional ways."

Geysen will describe these and other potential applications of combinatorial processes in an after-dinner talk on Thursday, Oct. 22.

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University of Delaware

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