Chemists have overcome a major hurdle by synthesizing a more stable form of heterocycle, a family of organic compounds that are a common component of most modern pharmaceuticals.
The research, which could expand the set of tools available to drug developers to improve drug safety profiles and reduce side effects, was published in Science by organic chemists from the University of British Columbia (UBC), the Massachusetts Institute of Technology (MIT), and the University of Michigan.
“Azetidines are a particularly useful and stable form of heterocycle, but synthesizing them has been incredibly challenging,” says 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.
However, many heterocycles currently used in drug design tend to oxidize under physiological conditions, which can lead to undesirable effects and problems with drug safety profiles.
Azetidines, organic compounds containing three carbon atoms and one nitrogen atom and liquid at room temperature, are known to be metabolically robust and do not undergo oxidation reactions under physiological conditions.
“This is something that synthetic organic chemists have been trying to accomplish for a long time, and we’re hopeful that this will allow researchers to develop new synthetic transformations of azetidines with more useful chemical and medical functions,” says Dr. Schindler, whose lab conducted the research at the University of Michigan with graduate student Emily Wearing and in conjunction with Dr. Heather Kulik’s lab at the Massachusetts Institute of Technology.
The team used light-driven reactions and a computational approach to solve the problem and, for the first time, succeeded in using compounds called imines productively in reactions to form new azetidines.