Waterloo chemists find new method for distinguishing mirror image molecules

Tuesday, March 22, 2022

Pharmaceutical drugs often take advantage of a specific shape in order to bind to the biological target. Some molecules, however, can exist with two versions that are mirror images of each other, similar to a left-handed and right-handed pair of gloves. In the body, often only one of the two molecules is an active pharmaceutical drug due to the difference in shape.

In a new study, University of Waterloo chemists have found a new way to analyze these mirror image molecules, known as chiral molecules, in order to distinguish the two different versions. This new technique could be used in the future to determine if a new potential medicinal molecule may be beneficial or not.

The researchers were studying a series of chiral drug molecules, including a high blood pressure medication called Verapamil, which has one carbon atom with chiral properties. They discovered that when they added a hydrogen ion to the nitrogen atom in the molecule, a second chiral centre is created. This nitrogen based chiral centre enables separation of the different chiral versions using a technique known as differential ion mobility spectrometry (DMS).

“When molecules like Verapamil are dissolved in water, the hydrogen ion that gets put onto the nitrogen atom hops around, and we don’t observe behaviour associated with chirality,” said Christian Ieritano, a chemistry PhD candidate and lead author of the study. “In our analysis, however, we isolate the molecule by itself in the gas phase, so there is no water present.”

Once all the water is removed, the hydrogen ion’s position is fixed creating the second chiral center in the molecule. At this point, DMS can separate the drug molecules based on the chirality introduced at the nitrogen centre and the chiral properties of the initial carbon chiral centre, such as the abundance of each mirror image version of the molecule, can also be studied.

“Chiral analysis is challenging and especially important when developing new drugs. In the worse case scenario, getting chirality wrong can be toxic to patients or cause mutations,” said Scott Hopkins, a professor of chemistry at Waterloo. “Normally, carbon comes to mind when we think of chirality in molecules, but here we show that protonation can induce chirality at non-carbon centres. We can take advantage of this phenomenon in a rapid analysis that doesn’t require any special sample preparation.”

“This is the first observation of protonation-induced chirality,” said Ieritano. “This chemistry provides an easy method of analyzing chirality, especially when it comes to small molecule drugs.”

The study, “Protonation-Induced Chirality Drives Separation by Differential Ion Mobility Spectrometry”, was published as a Very Important Paper and Frontispiece in the journal Angewandte Chemie. This work was a collaboration between the University of Waterloo and SCIEX.