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Boosting potential for drug discovery
Scientists now using diversity synthesis
By ELLEN GOLDBAUM
Contributing Editor
Call it combinatorial chemistry squared.
A team of UB organic chemists working on a fast, efficient and economical approach that boosts the power of combinatorial chemistry to produce astonishingly novel compounds has made an important technical advance that greatly facilitates its use and its commercial potential as a method for drug discovery and development.
"We now have the tools to do diversity synthesis," said Huw M. L. Davies, professor of chemistry and leader of the team, which is affiliated with the Strategically Targeted Academic Research (STAR) Center in Disease Modeling and Therapy Discovery at UB, sponsored by the New York State Office of Science, Technology and Academic Research.
Davies noted that like combinatorial chemistry, diversity synthesis techniques generate large families of compounds with potential biological activity.
The UB team's unique approach to diversity synthesis, based on combining breakthrough catalyst technology with new strategic reactions, results in a far more diverse array of chemical compounds with potential biological activity than the traditional combinatorial chemistry techniques.
On Oct. 15, at the Chiral USA conference in Boston, the team will report on its ability to immobilize a catalyst on a solid support made of tiny polystyrene beads, and to carry out chemical reactions on it.
A preliminary account of the work was reported in Organic Letters in July. The Web publication occurred on May 22.
"Doing combinatorial chemistry in the solid phase, as opposed to the liquid phase, is far preferable because it's so much easier to isolate the compound of interest from the other reagents in the reaction," Davies explained.
In the liquid phase, he said, tedious and time-consuming separation techniques have to be applied to isolate the compound of interest.
"On the other hand, with solid-phase reactions, the products can be isolated by a simple filtration process," he added.
The advance reported by the UB team in Organic Letters has been met with significant interest, Davies said, because the team succeeded in immobilizing the catalyst on a solid support without the benefit of a covalent linker.
"This is extremely unusual," said Davies. "Normally, you need a covalent linker to 'hook' the catalyst onto the support. The drawback with that scenario is that the covalent bond would change the catalyst.
"What's remarkable here is that since we haven't formed a covalent bond, the catalyst doesn't change, it just gets absorbed. Amazingly enough, the catalyst sticks to the solid support and works really well."
The UB team now is combining the new catalyst technology with new strategic reactions it has developed over the past few years, including one that overcomes what for the past 20 years has been considered the holy grail in organometallic chemistry—the ability to activate carbon-hydrogen bonds, normally considered "dead."
"It would take someone using traditional chemistry methods six months to generate these kinds of novel compounds and we can do it in a morning," said Davies.
The standard process of organic synthesis of pharmaceuticals involves altering reactive functional groups in a series of steps to arrive at the desired molecule. He noted, however, that when the number of steps are too numerous, it is no longer commercially viable.
"By activating the carbon-hydrogen bonds and avoiding the use of functional groups, very rapid entry to pharmaceutical targets is now possible," said Davies.
Because carbon-hydrogen bonds can occur throughout the structure of a molecule, Davies said, they are trickier to control.
"The really challenging part is figuring out how to control the one bond that you really want," he said. "With our catalyst, we get really nice selectivity."
The techniques already are responsible for the development of potentially beneficial new drugs in collaborations between Davies and colleagues at Roswell Park Cancer Institute and in a separate collaboration with colleagues at Wake Forest University.
Davies explained that pharmaceutical companies prefer to develop new chiral drugs (chiral meaning "handed") as a single isomer because opposite mirror images will have different biological effects and may even be harmful.
That concern may have had the unfortunate consequence, he said, of causing pharmaceutical firms to play it "too safe" in developing new drugs.
One of the central features of the new techniques of the UB group is that compounds are produced selectively as single mirror images.
"Our techniques act as enabling technologies, allowing scientists to readily access single mirror images of many classes of chiral compounds that are of interest to pharmaceutical companies," said Davies.
The success of these techniques rests on the very powerful chiral catalysts that have been developed by the Davies group.
"Small amounts of our catalysts can create huge amounts of the chiral products, making the process very economical," he said.
The combination of the new techniques with the ability to recover the solid supported catalysts greatly enhances the potential of this chemistry for a broad range of applications in diversity synthesis, said Davies.
This research was sponsored by NIH and supported by an unrestricted grant from Johnson and Johnson.