New reaction facilitates drug discovery
Medicines are becoming more precise and effective. Take, for example, new drugs that curb coronavirus replication at very specific times in the viral cycle. Nowadays, finding active compounds that have such a specific effect in the body usually relies on testing large libraries of chemical compounds. Therefore, an essential prerequisite for the development of even more effective drugs in the future is the expansion of existing libraries of active substances.
Scientists from the Laboratory of Organic Chemistry at ETH Zurich have now developed a simple and robust method to convert the indole group, which is commonly present in nature and drugs, into other important structural elements. The resulting classes of compounds have as broad a potential to exhibit a biological effect as their indole precursors; however, to date they have not been so widely considered in existing chemical libraries. The ETH chemists’ method will make it easy to add several new potentially active ingredients to libraries, streamlining drug discovery.
Basic structure of important substances
The indole ring as the central basic structure is present in hundreds of natural substances and medicines. Some representative examples are the amino acid tryptophan present in our proteins, the sleep hormone melatonin, the neurotransmitter serotonin – also known as the “happiness hormone” – and the rheumatism drug indomethacin. .
Like many other active core scaffolds found in biologically active compounds, the indole motif is made up of rings of atoms. Eight carbon atoms and one nitrogen atom are linked to form a skeleton in what is called an aromatic system, in this case made up of two fused rings. One of the rings consists of six carbon atoms and the other is a five-membered ring consisting of one nitrogen atom and four carbon atoms.
Scientists in the group of Bill Morandi, a professor in the Department of Chemistry and Applied Biosciences, have now found a way to extend the five-membered indole ring into a six-membered ring by inserting an extra nitrogen atom. Such a specific expansion of a ring scaffold sounds simple on paper, but in reality it has so far been a major challenge in the field. “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 adds value in a biological context – are extremely rare” , explains Morandi.
Old inspiration, new chemical trick
This new method was devised by Julia Reisenbauer, a doctoral student in Morandi’s group. Its inspiration was a chemical reaction developed in the 19th century: the Ciamician-Dennstedt rearrangement, named after its inventors, can be used to introduce an individual carbon atom into aromatic ring systems. However, getting a nitrogen atom to insert in a similar way was more difficult, so a new approach was needed: a hypervalent iodine reagent (one with an unusually high number of electrons) allowed the desired reactivity and a allowed the insertion of a “naked” nitrogen atom into the ring system.