What If the Drug Candidate That Didn’t Work Is Still Useful?

Drug development is a long, expensive process, often taking ten years or longer. During this process researchers synthesize tens of thousands of condidate molecules, and most never become medicines. A Florida State University scientist is part of a team proposing a practical way to provide some of these “dead-ends” with an opportunity to turn back into the useful starting materials for future successful pharmaceutical products.

Image credit: Parilov/Shutterstock.com

Assistant Professor Bryan Kudisch, who specializes in Chemistry and Biochemistry, along with his research team, has created a light-driven chemical process capable of converting a challenging category of compounds called sulfonamides into valuable components for future drug discoveries. This study was published in the Journal of the American Chemical Society.

Dr. Kudisch is a molecular spectroscopist who develops and applies laser-based techniques to measure extraordinary short time processes, particularly chemically important processes induced by light. His work demonstrates both exceptional technical ability and extraordinary insight to some of the most fundamental and complex processes in chemistry. This publication addressed an important problem closely related to drug discovery, which is a major strategic area of the FSU ASPIRE initiative.

Wei Yang, Chair, Department of Chemistry and Biochemistry, Florida State University

A Target for Repurposing Compounds

Sulfonamides, which are the foundational components of what are known as “sulfa drugs,” represent a significant category of molecular substructures in medicinal chemistry. Nearly 90 years ago, sulfonamide antibiotics were among the first antibacterial medicined to see widespread use. Currently, they continue to be incorporated into a range of pharmaceuticals that address various symptoms and diseases such as Type 2 diabetes, hypertension, HIV, and melanoma.

Although sulfonamides are beneficial in various pharmaceuticals, their chemical stability makes it challenging to find new applications for them. While chemists have created methods to transform numerous other functional groups that modify the biological characteristics of a compound, there are limited strategies available for sulfonamides - particularly concerning the sulfur atom that is central to these structures.

Eliminating this atom or substituting it with a different chemical group could enable scientists to develop novel variants of existing compounds, thereby maintaining their other advantageous features.

Kudisch and his team tackled this issue by employing a photochemical reaction that changes sulfonamides into anilines, which belong to a distinct class of chemical compounds that are crucial in the creation of certain cancer-fighting medicines. By editing a key part of the molecular framework, molecules that previously stalled out can become viable inputs for the next round of screening and optimization. 

This diagram describes how the new reported reaction allows the recycling of failed drug candidates by chemically transforming into quite different, but still bioactive molecules. Image Credit: Eric Nacsa

This outcome was achieved through a chemical ‘surgery’ that uses light to excise a sulfur atom from a sulfonamide. We’re optimistic these types of photochemical surgical tools could underpin a range of powerful processes for reshaping molecules that could advance the development of new medicines.

Bryan Kudisch, Assistant Professor, Chemistry and Biochemistry, Florida State University

How It Works: Light Transforming Molecular Structures

To pin down what happens during the light-triggered excision, Kudisch used advanced laser spectroscopy to follow the chemistry in real time. The team could observe events unfolding within a single picosecond or one millionth of a millionth of a second.

“We essentially spy on what the light is doing to sulfonamides,” Kudisch added. “Our research focuses on what photochemistry secrets are encoded in this transformation. We can track the molecules to understand how they transition into structures that eventually become the desired product or unwanted side product.”

Kudisch worked together with assistant professors of chemistry, Eric Nacsa and Elvira Sayfutyarova, at Pennsylvania State University and the pharmaceutical firm GSK on this research project. Kudisch’s team carried out experimental investigations to explore the mechanism of the reaction, while Sayfutyarova performed computational analyses to clarify the process of the reaction. Nacsa’s group identified and refined the reaction, showcased its diverse applications, and carried out further studies on its mechanism. GSK contributed by demonstrating the possible use of this new reaction in the field of drug discovery.

Experimental contributions from the Kudisch Lab at FSU combined with computational work by the Sayfutyarova group at Penn State were critical for understanding the reaction’s mechanism. We anticipate these results and ongoing collaborations with the Kudisch group will provide new fundamental insight into how light can transform molecular structures.

Eric Nacsa, Assistant Professor, Chemistry, Florida State University

Why It Matters: A New Tool for Drug Discovery

As structure-based drug design increasingly becomes vital for effective pharmaceutical development, this approach can significantly aid in the identification of new pharmaceuticals when utilized across various classes of compounds.

“We’re just scratching the surface in learning new ways to make, break and remodel molecules to make them do what we want them to do,” Kudisch further added. “There are so many fascinating opportunities in modern chemistry as long as you have the breadth of experience to understand how other chemists talk about their research and the depth of expertise to spot the beautiful new questions that come about with every discovery.”

Kudisch’s work also assist FSU Health, an academic health system that integrates the expertise of hospitals, doctors, clinics, research, education, and innovation to enhance the well-being of the community.