BUFFALO, N.Y. — In drug discovery, building complex molecules quickly is the name of the game.
Chemists want molecules with increasingly three-dimensional atomic structures because they may be more potent and selective inside the body, but the additional chemical steps needed to build that complexity cost time and money.
As it turns out, molecular complexity can be built in fewer steps using some surprisingly simple tools: off-the-shelf blue LED lights and a commercially available chemical building block familiar to sophomore organic chemistry students.
That's according to a new University at Buffalo-co-led study published Thursday (July 9) in Science .
The researchers mixed the familiar 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. That allowed the researchers to modify two adjacent carbon atoms instead of the usual one.
"We've used the relatively mild conditions of visible light to expand what chemists can do with a longtime organic chemistry staple," says corresponding author Patricia Z. Musacchio, PhD, assistant professor of chemistry in the UB College of Arts and Sciences. "We hope this gives chemists a faster route to the complex molecules needed in drug discovery."
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 National Science Foundation ACCESS program.
Two for one
Carbon atoms form the backbone of most small-molecule drugs. By changing what's attached to those carbon atoms, chemists can alter a drug's shape and behavior.
That's what makes molecules with carbon-halogen bonds such valuable starting points. A halogen atom can be readily removed from a carbon atom and replaced with another group of atoms, a reaction commonly taught in undergraduate organic chemistry.
Traditionally, the reaction only changes the carbon atom that the halogen was attached to. The neighboring carbon remains unchanged.
Musacchio and her team's method changes that. The photocatalyst temporarily opens a window for adding new groups of atoms to the neighboring carbon as well.
"The advantage is getting two modifications from a single reaction, whereas you normally 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 is crucial when creating small-molecule drugs."
Boxes of light
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, the blue LEDs activate the catalyst in each vial, beginning the reaction that ultimately allows two neighboring carbon atoms to be modified instead of one.
Using visible light is gentler than many traditional photochemical approaches that use higher-energy ultraviolet (UV) light.
"UV light could degrade or decompose the organic molecules that we're making, so the visible light is a much more mild approach," Musacchio says.
Musacchio says the approach could eventually be adapted for other types of molecular transformations as well. The team plans to work with pharmaceutical companies to explore how the method can be tailored to specific drug targets.
"The hope is to not only make drugs faster, but also make more complex drugs that can target more challenging medicinal goals," she says.
Other co-authors include David Watson, professor in the UB Department of Chemistry, as well as UB chemistry graduate students Yufei Zhang, Hammed Bisiriyu, Alon Nudler and Benjamin Parasch.
