In drug discovery, building complex molecules quickly is critical.
Chemists increasingly want molecules with three-dimensional atomic structures because they have the potential to be more potent and selective in the body, but the additional chemical steps required to build that complexity are time-consuming and expensive.
As it turns out, molecular complexity can be built in fewer steps using a surprisingly simple tool: an off-the-shelf blue LED light and off-the-shelf chemical building blocks familiar to second-year organic chemistry students.
That’s according to a new study co-led by the University at Buffalo published Thursday (July 9). science.
The researchers mixed familiar chemical building blocks – molecules with carbon and halogen bonds – with a light-activated catalyst. When illuminated with blue LED light, the catalyst temporarily converted the molecules to a more reactive form. This allowed the researchers to modify two adjacent carbon atoms instead of the usual single carbon atom.
We have taken advantage of the relatively mild conditions of visible light to extend what chemists can do with a long-standing staple of organic chemistry. We hope this will provide chemists with a faster route to the complex molecules needed for drug discovery. ”
Dr. Patricia Z. Musacchio; Corresponding author, Assistant Professor of Chemistry, UB College of Arts and Sciences
The study was conducted in collaboration with Worcester Polytechnic Institute, where Musacchio previously worked, and Binghamton University. This research was supported by the National Institute of General Medicine, part of the National Institutes of Health, and the National Science Foundation’s ACCESS program.
two people alone
Carbon atoms form the backbone of most small molecule drugs. By changing what is attached to these carbon atoms, chemists can change the shape and behavior of drugs.
This is why molecules with carbon-halogen bonds are a valuable starting point. Halogen atoms can be easily removed from carbon atoms and replaced with another group of atoms. This is a reaction commonly taught in undergraduate organic chemistry.
Traditionally, this reaction changes only the carbon atom to which the halogen was attached. Adjacent carbons remain unchanged.
Musacchio and her team’s approach changes that. The photocatalyst temporarily opens a window for adding new atomic groups to neighboring carbons as well.
“The advantage is that you get two modifications from one reaction, whereas normally you only get one,” said Jennifer Hirschi, Ph.D., associate professor of chemistry at Binghamton University, the study’s other corresponding author. “When creating small molecule drugs, it is very important to make more changes in fewer steps.”
box of light
Musacchio’s lab is filled with blue LEDs, the same lighting used in indoor gardens and aquariums.
The lights are installed inside a small compartment on the shelf that the team has dubbed the “Buffalo Box.” Inside these boxes, blue LEDs activate catalysts in each vial, starting reactions that can ultimately modify two adjacent carbon atoms instead of one.
The use of visible light is gentler than many traditional photochemical approaches that use high-energy ultraviolet (UV) light.
“Visible light is a gentler approach because ultraviolet light can degrade or break down the organic molecules we make,” Musacchio says.
Musacchio says the approach could eventually be applied to other types of molecular transformations. The research team plans to work with pharmaceutical companies to see how the method can be tailored to specific drug targets.
“The hope is not only to make drugs faster, but also to make more complex drugs that can achieve more difficult medical goals,” she says.
Other co-authors include UB chemistry professor David Watson and UB chemistry graduate students Yufei Zhang, Hammed Bisiriyu, Alon Nudler and Benjamin Parasch.
sauce:
Reference magazines:
Zhang, Y.et al. (2026) Contiguous disubstitution of alkyl CX synthons via alkene radical cation formation.. science. DOI: 10.1126/science.aef0766. https://www.science.org/doi/10.1126/science.aef0766
