Deuterium, an isotope of hydrogen, is being used to extend the lifetime of pharmaceuticals.
New research published in Angewandte Chemie International Edition proposes a new method of introducing deuterium into drugs. Led by Dr. Andreas Gansäuer, professor in the Kekulé Institute for Organic Chemistry and Biochemistry at the University of Bonn, a research team set about investigating a more effective way to introduce deuterium into drugs. Deuterium has been the subject of previous research since its substitution can slow down a drug’s degradation, allowing drugs to be taken less frequently or in smaller doses.
Deuterium’s effect on reactions is known as the kinetic isotope effect. Breaking down an active substance like a drug takes activation energy, as it doesn’t occur spontaneously.
"If you replace hydrogen with deuterium, the activation energy usually increases somewhat," explained Dr. Gansäuer. The same principle applies to the metabolism of medication in the body.
Replacing protium (the “normal” isotope of hydrogen) with deuterium is not so simple. Deuterium is costly, hard to come by, and it needs to be inserted with a precise orientation, which means accuracy is vital when incorporating the isotope into molecules. Gansäuer’s group addressed this issue by creating a new method of introduction using epoxides.
Epoxides are unique molecules because they contain a triangular ring of three atoms, two carbon, and one oxygen. The triangle of atoms is under immense tension, meaning they store potential energy just like a spring does. The team bonded an epoxide to their experimental drugs and then opened its ring using a catalyst. Once the ring was opened, two reactive ends were exposed. The catalyst carried a titanium and deuterium atom, so when the deuterium-titanium pair was exposed to the reactive ends, the deuterium bonded to one end of the open ring, and the titanium bonded to the other.
Success! The deuterium was transferred into the drug, and, importantly, it was in the correct orientation. In complex molecules, chemical reactions can occur in two different orientations— think of them as right- and left-handed versions of the same molecule. In pharmaceuticals, the orientation of molecules is essential to the drug’s efficacy since “mirror-image” molecules can have very different properties in the body and can be almost impossible to separate.
This discovery was an excellent example of harnessing the power of interdisciplinary collaboration, “combining the advantages of organometallic catalysis with those of radical chemistry.” Gansäuer’s group is looking forward to seeing this new method being used in future pharmaceutical production.
Sources: University of Bonn, Angewandte Chemie