Finding new life in old chemicals for pharmaceuticals
New method to modify sulfonamides, thousands of which exist in the chemical libraries of pharmaceutical companies, could open additional avenues for the development of new drugs
image: Pharmaceutical companies maintain libraries of chemical compounds that can be screened for use in the development of new drugs. A new photochemical technique, developed by a team led by Penn State chemists, can convert a class of these compounds, known as sulfonamides (bottom), which are difficult to modify for use beyond their initial purpose, into another useful type of compound, anilines (top left). The technique uses simple chemistry to recycle, reuse and repurpose failed drug candidate sulfonamides, which could open new pathways for drug development (top right).
Credit: Eric Nacsa, Penn State
UNIVERSITY PARK, Pa. — Drug companies maintain large libraries of chemical compounds that can be screened for potential use in the development of new pharmaceuticals. One class of these compounds, sulfonamides, is used in antibiotics and in drugs to treat type 2 diabetes, hypertension and inflammation. Thousands of these sulfonamides exist in these libraries, but their use beyond their initial purpose is limited because they are difficult to chemically modify. Now, new research, led by Penn State chemists, has uncovered a simple technique that coverts sulfonamides into another useful type of chemical group — anilines — used in other pharmaceuticals, including several cancer drugs. The technique could expand the utility of sulfonamides, potentially accelerating the development of new drugs, the researchers explained.
A paper describing the research appeared recently in the Journal of the American Chemical Society.
“Every drug that is brought to market usually requires a discovery campaign involving the preparation and biological evaluation of thousands and thousands of individual molecules, which are generally made over several synthetic operations,” said Eric Nacsa, assistant professor of chemistry in the Penn State Eberly College of Science and the leader of the research team. “So, we try to design synthetic processes that allow you to take simpler molecules that already exist or are easily purchasable and quickly convert them into what you want in fewer operations. The goal is to make those thousands and thousands of compounds, and ultimately get to the ideal optimized drug structure, in less time.”
The new method developed by the research team converts sulfonamides to anilines in a simple operation that involves two underlying events, Nacsa explained. First, they use the chemical compound potassium phosphate to remove a proton — the nucleus of a hydrogen atom — from the sulfonamide molecule. The sulfonamide, which is now short one proton, is then exposed to visible light, which initiates a chemical reaction to remove another part of the molecule, completing the conversion into an aniline.
“The ability to perform this chemical transformation without adding any further chemical catalysts was a total surprise,” Nacsa said. “The individual processes we used are all standard chemistry, but figuring out the details of why it works this way was a challenge.”
To do this, Nacsa teamed up with collaborators at Penn State as well as GlaxoSmithKline (GSK), a U.K.-based multinational pharmaceutical and biotechnology company, and Florida State University. The team showed how after the proton is removed, the light causes a nitrogen atom to bond to a carbon atom in the sulfonamide, clipping out sulfur dioxide (SO2) from the molecule.
“Removing the sulfur atom dramatically changes the biological properties of the compound,” Nacsa said. “Furthermore, GSK’s computational studies suggested that over 90% of commercially available sulfonamides could be modified using this technique. Expanding these chemical libraries using simple chemistry to recycle, reuse and repurpose sulfonamides will hopefully open new pathways for drug development.
The research team at Penn State included graduate students Jaxon L. Barney, Bhargav Patel, and Santino M. Servagno, as well as postdoctoral researcher Mrinmoy Das in Nacsa’s group, as well as graduate student Wyatt A. Gibbs and his advisor, Assistant Professor of Chemistry Elvira R. Sayfutyarova. Other key contributors were Alexander J. Reif, Brian J. Levandowski and Michael D. VanHeyst at GlaxoSmithKline in Collegeville, Pennsylvania; and Somnath Das and Assistant Professor of Chemistry Bryan Kudisch at Florida State University.
The work was funded by the Penn State Eberly College of Science and the U.S. National Institutes of Health’s National Institute of General Medical Sciences under grant R35GM155233. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders.