NEW SYNTHESIS METHOD PRODUCES POTENTIAL TREATMENT FOR COCAINE ADDICTION, OTHER POTENT BIOLOGICAL COMPOUNDS
ORLANDO -- A breakthrough in basic chemistry achieved by University at Buffalo scientists has the potential to expand dramatically the variety and potency of new, pharmaceutical compounds. So far, the chemistry, which is based on the use of a chiral -- or "handed" -- catalyst, is being applied by the UB team to develop a variety of new chemical structures.
Among them is a compound to treat cocaine addiction that is undergoing toxicological studies at the National Institute of Drug Abuse at the National Institutes of Health.
Another compound developed by the UB team developed has demonstrated success in animal studies as an antidepressant. The method is based on a convergent synthesis strategy, an extremely efficient synthesis method where two large structural components are brought together to create a compound.
This approach makes it possible to control the synthesis of a wide range of biologically important compounds with specific chemical structures, that, until now, could not be synthesized efficiently in the laboratory. A patent on the method has been filed.
The chemistry and some of the compounds that have been synthesized using it were described here today (August 27, 1996) at the national meeting of the American Chemical Society
"We have developed a powerful, flexible method of synthesizing very important building blocks in organic synthesis," said Huw M.L. Davies, Ph.D., professor of chemistry at UB and lead investigator.
One of the most biologically active groups of compounds to which the new synthesis method is being applied are the tropanes, which show very high selectivity in their interaction with various regions of the brain. Efforts to develop a chemical treatment for addiction to cocaine, which is a tropane, have been hampered in the past by the lack of a reliable synthetic method.
#012#Existing methods have involved either starting with cocaine itself, which limited the structure of the final compound, or have involved many steps and resulted in very low yields. According to Davies, a major challenge in contemporary chemistry is the controlled synthesis of chiral molecules. He explained that such syntheses are important because chiral molecules and their mirror images are different structures and each can display different properties, especially when interacting with living organisms. Pharmaceutical companies therefore prefer to develop new chiral drugs as a single isomer so they can avoid concerns about the possible negative interactions of the inactive mirror-image structure. However, many existing methods of synthesizing tropanes and other biologically important chemicals produce an equal mixture of the two isomers. By using a small amount of a chiral metal catalyst, the UB scientists have found a way to predetermine that only one structure -- and not its mirror-image -- will be produced.
"We have designed a chiral catalyst that allows us to synthesize a structure with a high preference for one of two chiral compounds," said Davies. He stressed that these advantages make the new chemistry applicable to a diverse array of biologically important compounds.
"Because of its flexibility, this chemistry will allow not only our group, but many other synthetic organic research groups, to make some obvious compounds that no one has been able to make before," he noted.
In addition to compounds developed by the UB team, Nobel Laureate E.J. Corey of Harvard University has used the UB method to synthesize the active isomer of the antidepressant sertraline.