University of Vienna: Chemists Achieve Breakthrough in Molecular Editing for Drug Discovery
Researchers at the University of Vienna have developed a new molecular editing method that allows one of the most important classes of chemical compounds, N-methylamines, to be directly converted into more complex structures. The breakthrough could significantly accelerate drug discovery by enabling hundreds of molecular variants to be generated quickly without the need for lengthy multi-step syntheses.
The research team, led by organic chemist Nuno Maulide at the University of Vienna, has introduced a new strategy that fundamentally changes how complex molecules can be modified. Instead of rebuilding molecules atom by atom, the method selectively replaces only a small part of an existing molecule, making it possible to rapidly create new chemical structures. The findings have been published in Nature Chemistry.
"Amines are everywhere. Proteins, drugs, neurotransmitters – practically all biological processes depend on amines. This makes the ability to directly and selectively modify such structures all the more important," said Uroš Vezonik, PhD student at the University of Vienna and co-first author of the study.
Nuno Maulide added: "Amines, with their special properties, are essential components of all structures of life. And because organisms interact so well with amines, non-natural amines also often have a significant impact on biological systems."
Editing Molecules Instead of Rebuilding Them
The study addresses a longstanding challenge in synthetic chemistry: the selective modification of secondary N-methylamines, compounds that are widely found in pharmaceuticals and biologically active molecules.
Traditionally, modifying these molecules required complex, multi-step syntheses or sensitive metal catalysts. The new approach instead performs what the researchers describe as an "Alkyl Swap", replacing the methyl group of an amine with substantially more complex molecular fragments using simple alkenes, readily available hydrocarbon compounds.
"What's fascinating is the simplicity," explained co-author Daniel Kaiser. "You can modify highly complex molecules at a very specific point without touching the rest of the molecule."
"Bathtub Chemistry" Under Mild Conditions
Unlike many modern amine functionalization methods that require oxygen-free environments, photocatalysts or highly sensitive reagents, the newly developed reaction proceeds under remarkably mild and straightforward conditions.
Maulide jokingly refers to the process as "bathtub chemistry": "The reaction is so simple that, in theory, you could even do it in a (heatable) bathtub. Of course, we still recommend a lab."
Giulia Iannelli, co-first author and former postdoctoral researcher in the Maulide group, noted: "This allows us to functionalize complex amines that could not be transformed in this way with any other known method. That's what makes this process so valuable."
New Opportunities for Drug Discovery
To demonstrate the versatility of the method, the researchers successfully modified numerous pharmacologically relevant compounds, including derivatives of the widely used medicines fluoxetine, duloxetine, sertraline, atomoxetine and citalopram. They also synthesized several commercially important drugs in a single reaction step.
The approach proved suitable for the late-stage modification of complex drug molecules, peptide functionalization, the synthesis of peptide-drug conjugates and the rapid generation of molecular libraries. These capabilities are particularly valuable in modern drug discovery, where hundreds of molecular variants often need to be evaluated during lead optimization.
A New Concept in Synthetic Chemistry
Beyond the specific reaction itself, the researchers believe the work introduces a fundamentally new way of thinking about molecular synthesis. Rather than relying on traditional aldehyde-based chemistry, the new strategy employs stable, readily available alkenes as starting materials for targeted molecular editing.
"What excites us most is the new way of thinking that this method enables," said Nuno Maulide. "Suddenly, molecules that were previously extremely difficult to synthesize become much more accessible."
The researchers conclude that what appears to be a deceptively simple reaction—combining an amine, an alkene and formaldehyde in a single vessel—has the potential to become an important new platform for molecular editing and pharmaceutical research.
Contact
Univ.-Prof. Dr. Nuno Maulide
Institute of Organic Chemistry, Faculty of Chemistry
University of Vienna
1090 Vienna, Währinger Straße 38
Email
+43 1 4277 52155
+43 664 60277 52155
organicsynthesis.univie.ac.at
Theresa Bittermann
Media Relations Manager
University of Vienna
1010 Vienna, Universitätsring 1
Email
+43 1 4277 17541