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Drug discovery is facilitated by a new reaction.

 Chemists at ETH Zurich have developed a simple procedure that enables the direct conversion of a widely used building block into many essential chemicals. This increases the potential for chemical synthesis and makes it easier to find novel pharmaceutically active components.


Drug discovery is facilitated by a new reaction.


The accuracy and effectiveness of medications are constantly improving. Nowadays, finding active substances that have such a particular impact on the body typically relies on testing vast chemical compound libraries. Expanding the existing libraries of active chemicals is thus a vital requirement for creating even more effective medications in the future.


Now, researchers from the Laboratory of Organic Chemistry at ETH Zurich have created a quick and reliable process for transforming the indole group, which is frequently found in nature and pharmaceuticals, into other crucial structural components. Although the resultant compound classes have not yet received as much attention in existing chemical libraries, they have a similarly vast potential for demonstrating biological function as their indole ancestors. The ETH chemists' approach will make it simple to add a number of new, potentially useful chemicals to the libraries, speeding up the drug discovery process. Science has published their research.



Basic structure of important substances

Numerous medicines and natural compounds share the indole ring as their fundamental core structure. Tryptophan, an amino acid found in human proteins, melatonin, a neurotransmitter also known as the "happy hormone" and the anti-rheumatic medication indometacin are a few notable examples.


The indole motif is composed of rings of atoms, like many other active core scaffolds discovered in biologically active chemicals. An aromatic system, which in this case consists of two fused rings, has a skeleton made up of eight carbon atoms coupled to one nitrogen atom. One of the rings has six carbon atoms, while the other has a five-membered structure with four carbon atoms and one nitrogen atom.


Researchers working with Bill Morandi, a professor at the Department of Chemistry and Applied Biosciences, have now discovered how to add an extra nitrogen atom to an indole to make it a six-membered ring. Although such a precise enlargement of a ring scaffold appears straightforward on paper, it has proven to be a significant difficulty in the field thus far. "Processes for adding a carbon atom to such a ring system have already been developed, but similar techniques allowing the insertion of a nitrogen atom—which often brings added value in a biological context—are extremely rare," says Morandi.



Old inspiration, new chemical trick

A doctorate candidate in Morandi's group named Julia Reisenbauer came up with this innovative technique. Her inspiration came from a 19th-century chemical process called the Ciamician-Dennstedt rearrangement, which may be utilized to add a single carbon atom into aromatic ring structures. A new strategy was required because it was more difficult to introduce a nitrogen atom into the ring system in a similar manner. The solution was to use a hypervalent iodine reagent (one with an unusually high number of electrons), which enabled the desired reactivity and permitted the insertion of a "naked" nitrogen atom into the ring system.


In the end, it was discovered that this approach is effective in a wide range of situations; in fact, it allowed the expansion of almost all of the indole compounds the chemists studied. The unusual robustness of our reaction, according to Reisenbauer, is a significant added benefit. Our method is tolerant of practically any other functional groups connected to the indole structure, unlike many other laboratory techniques. Depending on the design of the indole starting scaffold, the nitrogen atom can also be purposefully positioned at one of two locations within the new six-membered ring.


The method's potential is maybe even larger because preliminary research indicates that it may be able to modify indole core motifs in ways other than simply adding individual nitrogen atoms; the technique also appears to be applicable to other ring systems. According to Morandi and Reisenbauer, "Introducing nitrogen atoms into different aromatic ring systems could presumably produce many additional potential active ingredients,"


Numerous aromatic ring structures with nitrogen atoms are among the most crucial structural motifs in medicinal chemistry. Nitrogen atoms are one of the essential components in the chemistry of life. They guarantee that our DNA can accurately and dependably reproduce and retain our genetic information, among other things. These interactions and mechanisms also play a significant role in medicine, for example, in the development of antiviral and anticancer medications.




More information

Julia C. Reisenbauer et al, Late-stage diversification of indole skeletons through nitrogen atom insertion, Science (2022). DOI: 10.1126/science.add1383



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