Accelerating molecule design with a new technique capable of removing single atoms

A new technique offers a way to skip the laborious process of building molecular structures, allowing scientists to quickly and easily produce new molecules of interest.

University of Chicago chemists hope the breakthrough can help speed up drug discovery.

Every time a new cancer drug is announced, it represents hundreds of scientists who spend years behind the scenes working to design and test a new molecule. The drug must not only be effective, but also as safe as possible and easy to manufacture – and these researchers must choose from thousands of possible options for its chemical structure.

But building every possible molecular structure for testing is a laborious process, even if researchers just want to change a single carbon. atom.

A new technique published by chemists at the University of Chicago and pharmaceutical company Merck & Co. in the journal Science offers a way to skip this process, allowing scientists to quickly and easily produce new molecules of interest.

“It allows you to modify a complex molecule without having to start the design process all over again,” said Mark Levin, assistant professor of chemistry at UChicago and co-author of the new study. “Our hope is to accelerate discovery by reducing the time and energy spent on this process.”

bulldoze the house

As researchers consider a molecule, there are many tweaks they might want to test. Attaching a pair of hydrogen atoms instead of nitrogen atoms, for example, could make it easier for the body to absorb the drug. Perhaps removing a carbon atom would reduce a particular side effect. But making this new molecule can be surprisingly difficult.

“Even though it looks like a small switch on the surface, there are some things that can’t be fixed without going back to the beginning and starting from scratch,” Levin said. “It would be like talking to a contractor about redoing a bathroom in your house, and he says, ‘Sorry, we should tear down the whole house and start over. “”

Mark Levin and Jisoo Woo

Asst. Teacher. Mark Levin (left) and Ph.D. student Jisoo Woo at work in the University of Chicago lab. Credit: Jason Thome

Levin’s lab has set out to avoid this laborious process and allow scientists to make one or two modifications to a nearly finished molecule.

In this case, they wanted to be able to cut a single bond from a popular and useful class of molecules called quinoline oxides and turn them into another type of molecule called indoles. “Essentially, we want to extract a single carbon atom and leave everything else connected as if it was never there,” Levin said.

They came across an old technique from the 50s and 60s that uses light to catalyze certain reactions. It is not widely used today because the method was powerful but indiscriminate; mercury lamps used in the 1960s shone the full spectrum of light, triggering too many reactions in the molecule, not just the ones scientists were looking for.

But Jisoo Woo, a UChicago Ph.D. student and first author of the new paper, thought the results might be different with the newer LED lights that have become available over the past decade. These lamps can be programmed to emit only certain wavelengths of light.

It worked. By shining only one particular wavelength, scientists could only catalyze one particular reaction, which quickly and easily cut carbon bonds.

Levin, Woo and their colleagues wanted to know how useful this technique could be. They worked with Alec Christian, a scientist at the pharmaceutical company Merck, to test it on several different sets of molecules.

The technique has shown promise in several families of molecules.

“For example, we showed that we could take pitavastatin, a cholesterol drug, and turn it into another cholesterol drug called fluvastatin. They are two completely different molecules that are only linked by a carbon atom deletion,” Woo said. “Before this method, it had to be made from two entirely different processes and raw materials. But we were able to just take a drug and turn it into another drug in one transformation.

“It would be like talking to a contractor about redoing a bathroom in your house, and he says, ‘Sorry, we should tear down the whole house and start over. “”

Asst. Professor Mark Levin

Scientists hope this process can make the process of designing new molecules easier and faster, especially those that involve this particular transformation, which chemists call a “scaffolding jump.”

“There are all kinds of scaffolding jumps where it could end up with a very useful molecule, but the time it takes is just prohibitively expensive and the chemists never look at it,” Levin said. “There could be phenomenal drug compounds lurking there because teams just haven’t had time to start over.”

Christian agreed: “There are projects that I have seen come to a crossroads because someone wants to try a change like this, but it would take even a month to establish 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.

To conduct some of this research, the scientists used the ChemMatCARS beamline at the Advanced Photon Source, a massive X-ray synchrotron facility at the US Department of Energy’s Argonne National Laboratory.

Reference: “Scaffold hopping by net photochemical carbon deletion of azaarenes” by Jisoo Woo, Alec H. Christian, Samantha A. Burgess, Yuan Jiang, Umar Faruk Mansoor and Mark D. Levin, April 28, 2022, Science.
DOI: 10.1126/science.abo4282

Funding: Packard Foundation, National Institutes of Health, National Science Foundation, US Department of Energy.