A group of chemists with the University of Chicago has shown a new way to make a single-atom edit to a molecule, without changing any of its other components. The innovative method can be used to make a family of molecules known as pyrroles that includes many widely used medicines—and is significantly simpler, faster and more cost-effective than previous processes.

The inventors hope the method could help speed up the process of discovering new drugs.

Abigail Bracken, co-first author of the paper published Aug. 19 in Nature, said, “There are a lot of pyrroles that have never been made before, or have been made but are very expensive. We hope this opens up possibilities for both research and drug discovery.”

Pyrroles are one of those things that most people haven’t heard about, but that quietly make life on earth possible. For example, pyrroles form the basis of the heme that lets our blood carry oxygen and the chlorophyll that lets plants photosynthesise. 

However, they can be very difficult to synthesise in the laboratory, which limits how much experimentation can be done with them.

However, pyrroles have a set of molecules that are near-twins: another family of very common molecules called isoxazoles, whose makeups are almost identical except for a single atom. Where pyrroles have a carbon atom, isoxazoles have an oxygen atom. And they are much, much easier to make in the laboratory.

Alexa Lawrie, chemist and graduate student, and also a co-first author on the paper, said, “For example, for one of the molecules we made, the isoxazole version costs USD 11 per gram, but the pyrrole version of that molecule is USD 2,000 per gram.”

Bracken and Lawrie are members of the laboratory of Professor Mark Levin, which specialises in finding ways to make big changes to molecules more easily—an approach they call “skeletal editing.” Normally, if you’d like to make a new molecule, you have to start from scratch; the Levin lab designs techniques that allow scientists to quickly swap atoms in and out of existing molecules.

The team set out to see if they could find a way to directly turn isoxazoles directly into pyrroles, by swapping just a single atom.

After rigorous trial and error, they discovered a technique that significantly cuts the number of required steps and shortens the process to just 1 to 2 days. Unlike previous methods, the new process can also be completed in the same flask from start to finish.

The key turned out to be using a substitution reaction to attach a specific group of atoms containing 3 carbons—known as a propargyl group—to the ring, and then cutting the ring and replacing the oxygen atom with one of the new carbon atoms.

The find could be extremely useful for pharmaceutical scientists looking to develop new drugs, the team said.

“This means you can very quickly make a number of different pyrroles to test, which previously would have been time-consuming and expensive,” Lawrie added.

It’s also helpful for tests to determine which parts of molecules perform different actions, which is key knowledge for designing better drugs.

“If you can keep the ring the same and only change out one atom at a time, that could be very helpful for exploring how a drug works and which parts carry out which actions,” explained Bracken.

Members of the team plan to continue to expand the chemistry, they said.

“This method doesn’t work on every single variation, so it would be really interesting to expand the scope of the reaction,” said Lawrie.