UNC Chemists Develop Light-Powered Method to Build Key Drug Molecules Faster
A research team led by Dr. David Nicewicz, William R. Kenan, Jr. Distinguished Professor, found a way to use light, along with a special type of organic catalyst, to help create and customize a molecule, called piperazine, which plays a key role in a wide range of medicines, from antidepressants to cancer therapies.
April 22, 2025 | By Dave DeFusco
A team of chemists at UNC-Chapel Hill has developed a faster, more flexible way to build an important class of molecules used in many prescription drugs. Their breakthrough could help speed up drug discovery by making it easier for pharmaceutical scientists to experiment with and fine-tune these compounds.
Published in the Journal of the American Chemical Society, the research team’s study—led by Dr. David Nicewicz, William R. Kenan, Jr. Distinguished Professor, and UNC Ph.D. Chemistry students Jason Genova and Alexander Boley—found a way to use light, along with a special type of organic catalyst, to help create and customize a molecule, called piperazine, which plays a key role in a wide range of medicines, from antidepressants to cancer therapies.
“If you’ve ever taken a prescription drug, there’s a good chance piperazine was part of it,” said Boley, a lead author of the paper. “Piperazines are small, ring-shaped molecules that contain nitrogen atoms—think of them as tiny molecular scaffolds that hold other chemical parts in place. Because of their shape and properties, they help medicines interact effectively with the body.”
Despite their importance, most drugs that include piperazines use them in their simplest form. That’s because modifying the piperazine structure—adding chemical groups to different spots on the ring—is difficult with traditional methods. Chemists either have to start with a pre-built version of the molecule or go through several time-consuming steps, some of which require harsh chemicals or expensive metal-based catalysts.
“There’s been a real need for a more flexible, cleaner way to make custom versions of piperazines,” said Genova, the other lead author of the paper. “Our method opens up that possibility.”
The UNC team’s innovation lies in how they build the piperazine ring from scratch using a process called organic photoredox catalysis. In simpler terms, they use light—specifically, blue LED light—and a light-sensitive organic molecule, called a photocatalyst, to spark a series of chemical reactions.
Here’s how it works:
- Start with a simple building block: They begin with a type of molecule called a diamine, which has two nitrogen atoms.
- Add an aldehyde: This common chemical group helps form an intermediate molecule called an imine.
- Shine a light: The photocatalyst, when hit with light, temporarily gains energy and pulls an electron from the imine. This turns it into a high-energy radical, a molecule with an unpaired electron.
- Make the ring: That radical quickly folds in on itself and reacts with the other end of the molecule, forming the piperazine ring in a single step.
This light-triggered method is not only simpler and cleaner—it’s also programmable, meaning chemists can easily swap in different aldehydes or diamines to produce a wide variety of custom piperazines.
“Drug development is like trying to find the perfect key for a lock—chemists need to test many molecular keys to find the one that best fits a biological target, like a protein in the body,” said Dr. Nicewicz, senior author of the paper. “The more piperazine variations scientists can access, the more keys they can test.”
With the UNC team’s method, chemists can now make these variations more easily and in larger quantities. It also works well with a wide range of chemical ingredients, including those that would break down under older, harsher methods. That makes it useful not just for early-stage drug discovery, but potentially for making medicines on a larger scale.
The researchers successfully made piperazines with all sorts of attached chemical groups, including some based on natural products like lithocholic acid—a bile acid found in the body. They even showed that the process works with complex molecules and can be scaled up for use in industrial settings.
To take their method even further, the team created a two-step process that gives scientists even more control over the piperazine’s shape and properties. First, they use a reaction called hydroamination—another light-powered step—to build custom diamines. Then they feed these into their main piperazine-making process. This two-step approach lets chemists control exactly where new chemical groups are added on the piperazine ring—something that’s been very hard to do until now.
“The beauty of this method is how customizable it is,” said Boley. “We can now build piperazines with any pattern of substitutions that chemists might want to explore.”
The process works because of the unique chemistry of the photocatalyst. The team used a type of acridinium salt—a molecule that becomes highly reactive when excited by light. It pulls electrons from the starting material and sets off a controlled chain of reactions. The radical that forms doesn’t float away randomly—it’s carefully guided to fold into the piperazine ring.
As drug companies continue to explore new treatments for complex diseases, having access to a broader library of piperazine-based molecules could help lead to the next generation of breakthrough medicines.
“This is the kind of tool that medicinal chemists are always hoping for,” said Genova. “It lets you build the core you want, when you want it, without a lot of hassle.”