Atomic shift

Before a drug can be prescribed to the public, it has to undergo vigorous research and development that can take up to 12 years and an eye-watering cost of £1.15bn, yet tens of thousands of drugs a year are never licensed for use. The journey for any drug starts in a laboratory, researching diseases to understand their processes and pathways to identify a potential target for new treatments. From there, researchers will search for a particular molecule or compound that will act on this target and evaluate to find which structural modifications will impact the drug-like properties, such as binding affinity, potency, aqueous solubility and membrane permeability.

“It’s a long process,” explains Tyler Pearson, a postdoctoral researcher at the University of Chicago. Having earned his PhD in physical inorganic chemistry, Pearson initially found himself interested in chemical reactivity towards the end of his studies, which inevitably pushed him to pursue a postdoctoral position in a synthetic chemistry laboratory. And while he is keen to stress that his research is more focused on developing chemistry over actually developing new drugs – and “best left to pharmaceutical companies” – the application of the chemistry that he and his fellow chemists do is undeniable in the realm of drug development.

The process of building an atom requires researchers to go step by step as they screen for activity against a target of interest, Pearson explains. They then evaluate to determine which structural modification has an impact on the balance of its drug-like properties. However, over the years, researchers have found shortcuts through “privileged edits” that have relatively high success rates in improving drug-like properties.

One of these so-called edits is swapping a carbon atom with a nitrogen atom. A nitrogen atom can make all the difference in drug development; adding the atom might make it easier for a certain drug to reach the brain or avoid picking up the wrong proteins on the way to its target, for example. From imparting critical drug-like properties, introducing hydrogen-bond acceptors to managing oxidative metabolic liabilities, the effects of replacing a carbon atom with a nitrogen atom are so frequently observed in the field that it is commonly referred to as the ‘nitrogen effect’.

“Adding nitrogen to a drug can do a huge array of things,” continues Pearson. As a hydrogen bond acceptor, “it can mediate hydrogen-bonding interactions with the protein target of interest, or engage in intramolecular hydrogen bonding to impart conformational rigidity”. Adding the atom also enhances the polar surface area of a molecule, which can impact its water solubility and membrane permeability.

This process is easier said than done, however, as the hardest part is figuring out where the atom should go. “Its practice is divorced from this ideal by a conspicuous lack of direct atom-replacement techniques,” according to Pearson’s paper. “Conducting a nitrogen scan, therefore, almost invariably requires bottom-up synthesis of each azine isomer.” Put simply, if, as already mentioned, you consider that building an atom requires researchers to go step by step as they screen for activity against a target of interest, which are then evaluated to determine which structural modification makes an impact, if they get to the end and realise the drug molecule does not work the way they anticipated, the whole process has to start over from scratch to find the best spot for the nitrogen atom.

“You’ll often find that simply placing a nitrogen atom at one spot in a ring may not have the effect you want, but placing it in the next position over can have a huge effect. This necessitates the synthesis of every analogue, effectively ‘scanning’ nitrogen around a ring to find the best spot for it,” says Pearson. This is both expensive and time-intensive in drug development despite the conceptual simplicity of the ‘nitrogen scan’ and represents a bottleneck in the development of new medicines. It makes sense then that there has been interest in developing direct carbon-to-nitrogen replacement methods.

Making the switch

Recently, two studies have outlined potential methods for achieving direct replacement of atoms in a drug molecule, both from the University of Chicago and led by Mark Levin, associate professor of chemistry and senior author of each research paper. “Our goal was to circumvent this process with a C-to-N swap that was amenable to introducing nitrogen at a late stage,” says Pearson, lead author on ‘Aromatic nitrogen scanning by ipso-selective nitrene internalization’ in Science. “This would allow one to start from an advanced common intermediate to arrive at many different pyridyl isomers without resorting to completely rebuilding the molecule for each analogue you wanted to test.”

Replacing a carbon atom with a nitrogen atom has been a “wishlist” for many medicinal chemists for some time, Pearson explains, as there has previously been no way to achieve this swap before, which Pearson and the rest of the group saw as a challenge. “Reasoning that a net atom exchange would require successive atom insertion and atom deletion steps, we decided to address the problem in two steps.” The first step that Pearson and the research team took was to take advantage of well-established nitrene photochemistry that can insert nitrogen into benzene to form an azepine, a seven-membered heterocycle. From there, the challenge was to find a way to remove the correct carbon atom without scrambling the rest of the atoms on the molecule.

“After a lot of trial and error, we found that we could extrude a carbene from these heterocycles under unique oxidative conditions and to our delight it was selective for the ‘right’ carbon as well,” adds Pearson. He puts the main contributor to the success of their reaction down to an unconventional bromonium-based oxidant, which they are still trying to figure out why it was so important.

The other approach to this problem from the same lab, led by graduate student at the University of Chicago, Jisoo Woo, focuses instead on molecules that already have a nitrogen atom in the structure. As lead author of ‘Carbon-to-nitrogen single-atom transmutation of azaarenes’ in Nature, Woo’s method posits splitting the ring of atoms open using ozone and using the first nitrogen atom to guide the second one in.

Revolution requires evolution

While neither approach is perfect yet, both offer a way forward that could revolutionise drug development. The ability to replace a carbon atom with a nitrogen atom is a breakthrough discovery stated Levin. “We haven’t totally solved it, but we’ve taken two really big bites out of the problem and these findings lay a clear foundation for the future,” he said of the two methods. The studies offer the potential to make drug development easier, particularly for the researchers who are developing new drugs, saving them time and money by speeding up and simplifying the process.

The techniques described in both papers are also helpful as they match how researchers think when developing new drugs: “It’s a bit like typing on a computer instead of a typewriter,” said Levin. “It’s much easier on a computer as it lets you write the way you think, which is not always linear.”

“Our hope is that this reaction can enable medicinal chemists to do more nitrogen scans with less work overall,” explains Pearson. “This should help them more efficiently search chemical space for viable drug candidates.” While the reaction of the method isn’t complete, says Pearson, they are going to continue improving the proposed method and focus on tackling the issues at the top of the list that are related to expanding the scope of the reaction. This, he adds, involves making it work on more types of molecules.

Going forward, Pearson hopes that this method will be “enabling for medical chemists” in the development of new drugs, especially when nitrogen scans are normally impossible due to the complexity of the molecule. To Levin, both methods are a great example of creativity needed to make breakthroughs in chemistry, offering a “glimpse of something unusual” that gave them the foothold to work from.