In drug discovery, rapidly building complex molecules is the name of the game.
Chemists want molecules with increasingly three-dimensional atomic structures because they can be more potent and selective inside the body, but the additional chemical steps required to build this complexity cost time and money.
As it turns out, molecular complexity can be built in fewer steps using some surprisingly simple tools: blue LED lights and a commercially available chemical building block familiar to second-year organic chemistry students.
That’s according to a new University at Buffalo study published Thursday (July 9) at Science.
The researchers mixed the known chemical building blocks—molecules with carbon-halogen bonds—with a light-activated catalyst. When illuminated by blue LED light, the catalyst temporarily transformed the molecules into more reactive forms. This allowed the researchers to modify two neighboring carbon atoms instead of the usual one.
We have used the relatively mild conditions of visible light to extend what chemists can do with a long-standing basis of organic chemistry. We hope this will give chemists a faster route to the complex molecules needed for drug discovery.”
Patricia Z. Musacchio, PhD, the corresponding author, assistant professor of chemistry, UB College of Arts and Sciences
The work was done in collaboration with Worcester Polytechnic Institute, where Musacchio previously worked, and Binghamton University. It was supported by the National Institute of General Medical Sciences, part of the National Institutes of Health, and the ACCESS program of the National Science Foundation.
Two for one
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 a drug.
This is what makes molecules with carbon-halogen bonds such valuable starting points. A halogen atom can easily be removed from a carbon atom and replaced with another group of atoms, a reaction commonly taught in undergraduate organic chemistry.
Traditionally, the reaction changes only the carbon atom to which the halogen was attached. The adjacent carbon remains unchanged.
Musacchio and her team’s method changes that. The photocatalyst temporarily opens a window to add new groups of atoms to the neighboring carbon as well.
“The advantage is that you get two modifications from a single reaction, whereas you usually only get one modification,” says the study’s other corresponding author, Jennifer Hirschi, PhD, associate professor of chemistry at Binghamton University. “More changes in fewer steps are crucial when creating small molecule drugs.”
Light boxes
Musacchio’s lab is filled with blue LEDs—the same lights used for indoor gardens and fish tanks.
The lights sit inside small compartments on shelves that the team has dubbed “Buffalo boxes.” Inside these boxes, blue LEDs activate the catalyst in each vial, starting the reaction that eventually allows two adjacent carbon atoms to be modified instead of one.
The use of visible light is milder than many traditional photochemical approaches that use higher energy ultraviolet (UV) light.
“Ultraviolet light could degrade or decompose the organic molecules we produce, so visible light is a much gentler approach,” says Musacchio.
Musacchio says the approach could eventually be adapted for other types of molecular transformations. The team plans to work with pharmaceutical companies to explore how the method can be adapted to specific drug targets.
“The hope is not only to make drugs faster, but also to make more complex drugs that can target more challenging medical targets,” he says.
Other co-authors include David Watson, a professor in the UB Department of Chemistry, as well as UB chemistry graduate students Yufei Zhang, Hammed Bisiriyu, Alon Nudler and Benjamin Parasch.
