An unexpected side result of the group's initial work was the discovery that the structure previously reported for the biyouyanagins was slightly off. With the proper structures in hand, the Nicolaou team recognized it could induce formation of critical bonds that join the two domains of the molecules by bombarding the right chemical building blocks with ultraviolet light.
This technique, known as photocycloaddition, allowed the scientists to synthesize the two known biyouyanagins as well as a third type not yet discovered in nature. The scientists then began combining a variety of different building blockssome commercially available and others they produced in the labusing the photocycloaddition to build a library of about 50 analogs, compounds similar to the originals but with significant chemical variations.
The resulting compounds then went in groups to various collaborating Scripps Research laboratories. Professor Dennis Burton's lab analyzed the compounds' ability to inhibit replication of HIV. Chair of the Department of Chemical Physiology Ben Cravatt's team looked at anti-inflammatory potential. Professor Juan de la Torre's group examined effects against LCMV, the prototype member of the arenavirus family that includes several causative agents of deadly hemorrhagic fever disease in West Africa and South America.
All of the compounds in the team's new library are, like aspirin, considered small molecules. Nicolaou believes these offer the best biomedical potential. Larger molecules such as proteins are finding new medical applications, but have to be injected and are often short-lived and very expensive.
"If you can discover small molecules that work, they're affordable and they last long enough in the body to do their jobs," he said. "Those are the magic bullets."
|Contact: Mika Ono|
Scripps Research Institute