Accelerating drug discovery with a single carbon atom

Nitrogen atoms and nitrogen-containing rings, known as heterocycles, play crucial roles in the development of medicines. A research team led by OU Presidential Professor Indrajeet Sharma has found a way to change these rings by adding just one carbon atom using a fast-reacting chemical called sulfenylcarbene. This method, called skeletal editing, transforms existing molecules into new drug candidates.

"By selectively adding one carbon atom to these existing drug heterocycles in the later stages of development, we can change the molecule's biological and pharmacological properties without changing its functionalities," he said. "This could open uncharted regions of chemical space in drug discovery."

Previous studies have demonstrated a similar concept but relied on potentially explosive reagents, exhibited limited functional group compatibility, and posed significant safety concerns for industrial-scale applications.

Sharma's team has developed a bench-stable reagent that generates sulfenylcarbenes under metal-free conditions at room temperature, achieving yields as high as 98%. Avoiding metal-based carbenes helps reduce environmental and health risks because many metals are known to have some level of human toxicity.

The researchers are also exploring how this chemistry could revolutionize a fast-growing area in pharmaceutical science known as DNA-encoded library (DEL) technology. DEL platforms allow researchers to rapidly screen billions of small molecules for their potential to bind to disease-relevant proteins.

The metal-free, room-temperature conditions of the team's new carbon insertion strategy make it a compelling candidate for use in DNA-encoded libraries. Unlike other reactions that need harsh chemicals or high heat, this new method works in water-friendly liquids and is gentle enough to use with molecules attached to DNA.

By enabling precise skeletal editing in collaboration with the Damian Young group at the Baylor College of Medicine, Sharma's approach could significantly enhance the chemical diversity and biological relevance of DEL libraries. Importantly, these are two key bottlenecks in drug discovery.

"The cost of many drugs depends on the number of steps involved in making them, and drug companies are interested in finding ways to reduce these steps. Adding a carbon atom in the late stages of development can make new drugs cheaper. It's like renovating a building rather than building it from scratch," Sharma said. "By making these drugs easier to produce at large scale, we could reduce the cost of healthcare for populations around the world."