Researchers have presented a method that allows the heavier hydrogen “brother” deuterium to be specifically introduced into many different molecules. The deuterated compounds thus obtained are more stable with respect to degradation by certain enzymes. Drugs produced using this method may be effective for longer, which means they need to be taken in lower doses or less frequently.
Hydrogen (abbreviated “H”) is the lightest of all the elements. It usually consists of only one positively charged proton and one negatively charged electron and is also referred to as protium in this form. But there are also two heavier hydrogen isotopes, deuterium and tritium. The deuterium nucleus contains a neutron in addition to the proton, in the case of tritium there are even two. Both are very rare; tritium is also, unlike deuterium and protium, radioactive.
Deuterium has been at the center of pharmaceutical research for a few years now, as it can ensure that drugs break down 5, 10, or even 50 times slower. “We call this the kinetic isotope effect,” explains Prof. Andreas Gansäuer from the Kekulé Institute for Organic Chemistry and Biochemistry at the University of Bonn (Germany). The reason is that many reactions, including the degradation of active substances, do not occur spontaneously. They first need a slight “push”, the energy of activation. It’s a bit like driving a miniature car up a hill: this too only works if the car has enough momentum. “If you replace hydrogen with deuterium, the activation energy usually increases somewhat,” Gansäuer explains. “As a result, reactions are slower. This also applies to the metabolism of pharmaceuticals in the liver.
Triple tension rings
This means that the introduction of deuterium instead of protium in drugs makes them have a longer effect. They can therefore be taken in lower doses or less frequently. However, deuterium is rare and therefore relatively expensive. Therefore, deuterium should ideally only be introduced at points where metabolization predominantly occurs. This is where the new process comes in.
It is based on a class of substrates called epoxies, which can now be produced almost at will in different ways. These groups can be visualized as a kind of “triangle” in which two corners are formed by carbon atoms and the third by an oxygen atom. Such three-link rings are put under great tension, which means that they easily tear on one side. Epoxies therefore store energy like a stretched spring, which can then be used for certain reactions.
“We introduced epoxies into different test molecules and then opened the stretched ring with our catalyst,” explains Gansäuer. “This contains a titanium atom to which deuterium is bonded.” To put it figuratively, when the epoxy ring is opened, two reactive ends are created. The catalyst binds to one of them, which then transfers the deuterium to the remaining free end in a second step. “This allows us to introduce a deuterium atom in one place and with a very specific and desired spatial orientation,” Gansäuer explains. He is a member of the transdisciplinary research area “Building Blocks of Matter and Fundamental Interactions” (TRA Matter) at the University of Bonn.
Another advantage of the method is that for many complex molecules, there are two different ways of bonding which mirror each other. The new process can be used to create almost exclusively one of the two shapes. “As the compounds of mirror-image molecules are very difficult to separate and, moreover, they often have different properties in the human body, such stereoselectivity is very important,” comments Gansäuer.
The developed method has been used, for example, to produce deuterated precursors of the analgesic ibuprofen and the antidepressant venlafaxine. The authors are confident that it will be applied to many other pharmaceuticals in the future.