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Two Methods Simplify Atom Swapping in Drug Development

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The development of two new methods to swap carbon atoms for nitrogen atoms in drug molecules – a common problem in pharmaceutical chemistry – could make it easier to develop new drugs. The two studies by University of Chicago chemists are published in Science and Nature.

Tiny changes can make a huge difference

When designing new pharmaceutical drugs, chemists may often want to swap out one particular atom to change the molecule’s properties – but this is not necessarily a simple task. Molecules are built step by step, and if one particular atom needs to be changed, the whole molecule must go back to the drawing board and the entire process starts again.

“There’s a cost–benefit analysis that comes into play,” said Dr. Tyler Pearson, postdoctoral researcher at the University of Chicago and first author on the Science study. “Is it worth it to start over? Or do you just go with what you have?”

But what if there is a way that chemists could easily swap one atom for another?

“This is the grand-challenge problem that I started my lab to try to solve,” said Dr. Mark Levin, the senior author of both papers and associate professor of chemistry at the University of Chicago. “We haven’t totally solved it, but we’ve taken two really big bites out of the problem, and these findings lay a clear foundation for the future.”

Tackling a common problem in drug development

The focus of Levin’s research is to find new ways to make subtle changes to the foundations of a molecule without starting from scratch.

Single atoms can be hugely important in the chemistry of a molecule – drug molecules can act in very different ways if, say, a carbon atom was swapped out for a nitrogen atom. These subtle changes could make it easier for the new molecule to pass through the blood–brain barrier, or less likely to bind to the wrong targets. Swapping a carbon atom for a nitrogen atom isn’t an easy task, and existing methods have had limited success. If the reaction accidentally moves a different atom, the molecule can lose its desired effect.

“You might accidentally delete the wrong carbon in the molecule, and this causes the rest of the molecule to shift,” said Jisoo Woo, a graduate student and the first author on the Nature study. “This can have a huge impact on how well the final molecule works.”

The researchers set to work developing two different but complementary methods to tackle this problem.

Offering a way forward

Woo’s method, described in Nature, is designed to work for molecules with nitrogen atoms already nearby in their structure. Ozone is used to open the molecule’s ring-like structure and replace a single carbon atom with a nitrogen atom.

The second method, led by Pearson and outlined in Science, works for molecules that do not already have a nitrogen atom, simply removing the desired carbon atom and replacing it with a nitrogen atom.

The authors acknowledge that neither method is perfect, but that they may offer a meaningful way forward that aligns with how new drugs are already designed, and both methods required a degree of serendipity and creativity.

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“It’s a bit like typing on a computer instead of a typewriter,” said Levin. “It’s much easier on a computer because it lets you write the way you think, which is not always linear.”

“To me, this is a great example of the creativity that you need in order to make breakthroughs in chemistry,” Levin continued. “In both we had precipitating events that gave us a glimpse of something unusual, and that gave us a foothold we could work from.”


Woo J, Stein C, Christian AH, Levin MD. Carbon-to-nitrogen single-atom transmutation of azaarenes. Nature. 2023;623(7985):77-82. doi: 10.1038/s41586-023-06613-4

Pearson TJ, Shimazumi R, Driscoll JL, Dherange BD, Park DI, Levin MD. Aromatic nitrogen scanning by ipso-selective nitrene internalization. Science. 2023;381(6665):1474-1479. doi: 10.1126/science.adj5331

This article is a rework of a press release issued by the University of Chicago. Material has been edited for length and content.