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.
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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