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Breakthrough in Controlling the 3D Structure of Molecules

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New drug discovery has long been limited by researchers’ inability to precisely control the 3D structure of molecules. But a team led by scientists from The Graduate Center of The City University of New York (GC/CUNY) has made a major breakthrough in chemical synthesis that now makes it possible to quickly and reliably modify the 3D structure of molecules used in drug discovery, according to a paper appearing in the current issue of the journal Science.

The researchers’ work builds on the Nobel Prize-winning discovery by chemist Akira Suzuki, who pioneered the development of cross-coupling reactions, which use palladium catalysts to form bonds between two carbon atoms. The method can be used to create novel molecules with medicinal or industrial applications. Suzuki’s original discovery has enabled the rapid construction of new drug candidates, but is largely limited to the construction of novel flat (or 2D) molecules. That limitation has prevented scientists from easily manipulating the 3D structure of molecules during the drug development process.

“Two molecules that have the same structure and composition but are mirror images of each other can produce very different biological responses. Therefore, controlling the orientation of atoms in the 3D structure of molecules is critical in the drug discovery process," said research project director and corresponding author Mark Biscoe, who is an associate professor of chemistry with GC/CUNY and The City College of New York. “The thalidomide tragedy in the 1950s and ’60s arose because of the different biological effects of the two mirror images of thalidomide. Today, cross-coupling reactions are employed extensively in drug discovery, but they haven’t enabled 3D control of molecular structures. Our team has developed a new process to achieve this control, which permits the selective formation of both mirror images of a molecule.”


To accomplish their goal, the GC/CUNY researchers collaborated with researchers from The University of Utah to develop statistical models that can predict reaction outcomes of chemical processes. They then applied these models to develop conditions that enable predictable control of 3D molecular structure. Key to their research was understanding the effects of different phosphine additives on how palladium promotes cross-coupling reactions. The goal was to be able to preserve the 3D geometry of the initial molecule during a cross-coupling reaction, or to invert it to produce its mirror image. “By understanding how different phosphine ligands influence the final geometry of cross-coupling products, we were able to develop reliable methods for selectively retaining or inverting the geometry of a molecule,” said first author Shibin Zhao, a GC/CUNY Ph.D. student with Biscoe’s group. “This means we’re now able to control the final geometry of a molecule more efficiently.”


The work of Biscoe and his colleagues addresses a significant challenge in the drug-discovery process. Previously, palladium-catalyzed cross-coupling reactions enabled the rapid production of libraries of predominately flat molecules for biological testing. With this new method, scientists will now be able to use cross-coupling reactions to rapidly generate libraries of new compounds while controlling the 3D architecture of the compounds. Easy access to such structurally diversified compounds will facilitate efforts to discover and develop new medicines.

This article has been republished from materials provided by The Graduate Center of The City University of New York (GC/CUNY). Note: material may have been edited for length and content. For further information, please contact the cited source.