A new method of molecular manipulation is being developed that allows scientists to make one-atom changes within a day and without the need to rebuild the molecule. The goal is to accelerate the drug manufacturing process.

“By late-stage development, scientists have a preliminary molecule whose drug-like properties are promising, but not quite good enough for the clinic,” says Mark Levin, PhD, assistant professor at the University of Chicago. Small tweaks to the molecular structure are needed to improve properties, but chemists lack the tools to make those changes. “Therefore, they go back to commercially-available building blocks each time and build up new, structurally similar molecules over and over to get the right properties. That’s an incredible waste [of time and effort].”

Levin’s lab demonstrated a method to delete single carbon atoms from organic molecules and accelerate drug discovery. In a recent paper in Science, he outlined this scaffold-hopping approach.

The goal was to break a carbon bond in the quinoline N-oxide class of molecules, leaving everything else intact. Observations from papers published in the mid-20th century provided the clues that led Jisoo Woo, Levin’s PhD student and the paper’s first author, to use light to promote specific reactions. He realized that the mercury lamps used in the 1960s emitted full spectrum light, leading to multiple, often unwanted, reactions. Modern LEDs, however, can be tuned to emit only specific wavelengths of light to promote a single reaction.

The method reported in Science allows “chemists to hop directly between chemically distinct heteroaromatic scaffolds,” the authors write, by using “selective photolysis of quinoline N-oxides with a 390 nm light followed by acid-promoted rearrangement.” This narrow-wavelength and acid treatment method enable the precision that was not possible with full spectrum light.

This technique appears to work with many families of molecules and, in tests, transformed the cholesterol drug pitavastatin into the related cholesterol drug fluvastatin.

“There are a host of different atom deletions and insertions you might want when tweaking molecules,” Levin says. Therefore, his lab is developing multiple reactions to enable precise, single-atom manipulation of late-stage molecules.

One approach enables scientists to delete one atom and insert another in the same or a different location. “That helps you rearrange the structure of the molecular scaffold in interesting ways,” he points out. “As more of these tools are developed, their combinations will allow scientists to manipulate molecules in ways that are more powerful than any one of them alone.”

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