Speeding Up Molecule Design With a New Technique That Can Delete Single Atoms

Every time a new cancer treatment is introduced, it is the result of years of labor by hundreds of scientists to develop and test a brand-new chemical. These researchers must select from among thousands of potential alternatives for the chemical structure of the medicine in order for it to be not only efficient but also as safe and simple to manufacture as feasible.

Even if scientists only wish to alter a single carbon atom, creating every potential chemical structure for testing is a time-consuming operation.

By skipping ahead of that procedure, researchers from the University of Chicago and Merck & Co. have developed a new approach that enables rapid and simple creation of novel molecules of interest.

“This allows you to make a tweak to a complex molecule without having to start the design process entirely over,” said Mark Levin, assistant professor of chemistry at UChicago and co-author on the new study. “Our hope is to accelerate discovery by reducing the time and energy that goes into that process,” stated Mark Levin, assistant professor of chemistry at UChicago and co-author on the new study. 

Bulldozing the house

There are several adjustments that scientists may wish to explore while thinking about a chemical. For instance, substituting a pair of hydrogen atoms for nitrogen atoms might facilitate the drug's absorption by the body. It's possible that eliminating one carbon atom would lessen a specific negative effect. However, creating that novel molecule might be quite challenging.

“Even though it looks on the surface like a tiny switch, there are certain things that are not fixable without going all the way back to the beginning and starting from scratch,” Levin explained. “It’d be as if you were talking to a contractor about redoing one bathroom in your house, and he says, ‘Sorry, we’d have to bulldoze the entire house and start over.’” 

The objective of Levin's lab is to avoid this time-consuming procedure and enable researchers to make one or two modifications to a nearly completed molecule.

In this case, they sought to be able to convert quinoline oxides—a well-known and practical class of molecules—into indoles, a different class of molecule. “Essentially, we want to pull out a single carbon atom and leaving everything else still connected as if it was never there,” according to Levin.

They discovered an antiquated method from the 1950s and 1960s that makes use of light to activate certain reactions. The procedure was effective but indiscriminate; the mercury lamps used in the 1960s blasted out the complete spectrum of light, setting off too many processes in the molecule—not just the ones the scientists sought. As a result, it isn't frequently employed today.

However, Jisoo Woo, a Ph.D. candidate at the University of Chicago and the paper's primary author, believed that given the availability of more modern LED bulbs during the past ten years, the outcomes may have changed. These lights may be set to exclusively emit particular light wavelengths.

It succeeded. The researchers were only able to catalyze one specific reaction, which swiftly and readily broke the carbon bonds, by illuminating a certain wavelength.

Levin, Woo, and their associates were interested in determining how broadly applicable this method may be. To test it on several sets of compounds, they collaborated with Alec Christian, a scientist at the pharmaceutical firm Merck.

Across a number of chemical families, the method showed potential.

“For example, we showed we could take the cholesterol drug pitavastatin and turn it into another cholesterol drug called fluvastatin. These are two completely different molecules only related by one carbon atom deletion,” Woo remarked.

“Before this method, you would have to make it from two entirely different processes and starting materials. But we were able to just take one drug and turn it into another drug in one transformation.”

The researchers are hopeful that this procedure would simplify and expedite the creation of novel compounds, particularly those involving this specific transition, or "scaffold hop," as it is known to chemists.

“There are all kinds of scaffold hops where it could result in a very useful molecule, but the time involved is just prohibitive and so chemists never look at it,” noted Levin. “There might be phenomenal drug compounds are hiding out there because teams just couldn’t get the time to start over.”

“There are projects I’ve seen come to a crossroads because someone wants to try a change like this, but it would take a month to even work out the initial chemistry. Whereas with this process, you could have your answer in a day. I think a lot of people will want to use this method,” said Christian.

The ChemMatCARS beamline at the Advanced Photon Source, a massive X-ray synchrotron facility at the Argonne National Laboratory of the U.S. Department of Energy, was used by the researchers to carry out a portion of this study.