The research could help drug developers improve the safety profiles of drugs

Research from the University of British Columbia, MIT and the University of Michigan could help drug developers improve drug safety profiles and reduce side effects.

Chemists have overcome a major hurdle in synthesizing a more stable form of the heterocycle—a family of organic compounds that are a common ingredient in most modern pharmaceuticals.

The research, which could expand the toolbox available to drug developers to improve drug safety profiles and reduce side effects, was published in Science by organic chemists at the University of British Columbia (UBC), Institute of Technology Massachusetts (MIT). and the University of Michigan.

“Azetidines are a particularly useful, stable form of heterocycle, but their synthesis has been incredibly difficult.”

Dr. Corinna Schindler, Canada Research Chair in Synthetic Solutions for Bioactive Compounds at UBC and senior author on the paper

Heterocycles play an important role in the design of modern drug families, including anticancer drugs and antibiotics. Some reviews indicate that 85 percent of all biologically active chemical entities contain a heterocycle.

But many heterocycles used today in pharmaceutical design tend to oxidize under physiological conditions. This can lead to off-target effects and challenges with drug safety profiles.

Azetidines—organic compounds that contain three carbon atoms and one nitrogen atom and are liquid at room temperature—are known to be metabolically stable and do not undergo oxidation reactions under physiological conditions.

“This is something that synthetic organic chemists have been trying to achieve for a long time, and we hope that this will allow researchers to develop new synthetic transformations of azetidines with more useful chemical and medicinal functions,” says Dr. Schindler, whose lab conducted research at the University of Michigan with graduate student Emily Wearing and in conjunction with the lab of Dr. Heather Kulik at the Massachusetts Institute of Technology.

The team used light-driven reactions and a computational approach to the problem and for the first time were able to engage compounds called imines productively in reactions to form new azetidines.