Scientists talked about a new way to replace carbon with nitrogen in molecules.

Researchers led by Mark Levin, a chemist at the University of Chicago, have developed a way to replace a carbon atom with nitrogen in complex organic molecules. The reaction proceeds under relatively mild conditions and makes it possible to obtain new variants of compounds of interest for drug development. One of the created vinpocetine analogues in laboratory tests showed an improvement in solubility and a number of other characteristics. Why chemists change individual atoms in molecules, how blue light helps to carry out such a reaction and what new technology can give to pharmaceuticals — in the Izvestia material.

Why can one atom matter?

The search for a new drug does not always begin with the creation of a completely unfamiliar molecule. Sometimes researchers take a compound with an already known biological activity and change its structure to see if individual properties can be improved.

One of these techniques is to replace a carbon atom with nitrogen. Even a small change in the molecular framework can affect the characteristics of a substance. Therefore, chemists obtain different analogues of the starting compound and compare them with each other.

In the new work, this approach was tested, among other things, on vinpocetine. For one of its derivatives, atom replacement was accompanied by improved solubility and metabolic characteristics, as well as less impact on a protein important for heart function. However, it is impossible to guarantee a useful result in advance. Atom replacement is a search tool that allows you to obtain a new molecule for testing. Its properties must then be measured separately.

What is molecular skeleton editing?

The methods by which scientists change the atomic composition of the basic framework of a molecule are called skeletal editing. In this case, the task was to replace carbon with nitrogen in the aromatic ring of a complex compound.

Such transformations are already known to chemists, but previous approaches have limitations. Some require strong oxidizing agents, while others are suitable only for certain molecular structures. This makes it difficult to apply them to complex substances that are sensitive to reaction conditions.

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The authors of the new work sought to expand the range of available compounds. The method allows for the substitution of a number of two-ring aromatic systems in the benzene fragment, including indoles, benzofurans, and benzothiophene. The mild conditions made it possible to work with complex natural compounds. This is essential for medicinal chemistry: a successful reaction on a simple model molecule does not mean that the same technique is suitable for a substance with a more complex structure.

How does the blue light reaction work?

For the transformation, the researchers used pre—prepared molecules with an azide group, a fragment containing three nitrogen atoms. They were then exposed to blue light in the presence of oxygen and a tetramethylthiourea reagent.

Irradiation triggers the formation of a reactive intermediate particle, nitrene. Next, a sequence of transformations takes place, during which the original ring opens. Subsequent chemical treatment allows you to close the ring again. In the resulting structure, nitrogen appears in place of one of the carbon atoms.

Thus, the method includes preparation of the initial compound, a photochemical stage, and final processing. It is not limited to a simple irradiation of a ready-made medicine.: to obtain a new analogue, a certain sequence of chemical reactions is required.

How an obstacle was turned into a working mechanism

The main feature of the approach is related to the state of the nitrene. In previous reactions, it was required that this intermediate particle be in a singlet state. However, it could transition to another, triplet state, in which the necessary restructuring did not occur.

The singlet and triplet states are distinguished by the structure of the particle's electronic system. For chemists, this is of practical importance: it depends on the state in which it can enter into reactions. Levin's team proposed using triplet nitrene in another transformation pathway. What hindered the previous process became part of the new mechanism.

This approach made it possible to replace carbon with nitrogen in complex compounds for which previous methods were of limited use. At the same time, we are talking about expanding the possibilities of the reaction, and not about a way to edit any organic molecules.

What have the experiments with vinpocetine shown?

The researchers tested the method on dozens of compounds from several groups of ring molecules. Examples include the antiarrhythmic drug dronedarone, as well as the pharmacologically active substances vinpocetine, yohimbine and katarantin.

These experiments have shown that the reaction can work with complex structures. Of particular interest was the comparison of the properties of one of the new vinpocetine analogues with the starting material. In preliminary laboratory tests, the derivative turned out to be more soluble and demonstrated improved metabolic characteristics. In addition, it had a weaker effect on one of the proteins important for heart function.

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The latter observation is potentially significant for assessing the risk of cardiac arrhythmias. However, a lower effect on a single protein in a laboratory test does not prove that the new compound is safer for humans. For such a conclusion, it is necessary to investigate its effect in the body.

The original message also does not provide confirmation that the resulting analogue is better at treating any disease. So far, a change in individual properties of the molecule has been shown, which is of interest for further verification.

What the method can give to drug developers

The practical value of the work lies in the ability to obtain and explore new variants of complex compounds. The more suitable structures available to chemists, the wider the choice of molecules for subsequent comparison.

At the same time, successful laboratory synthesis and industrial production solve different problems. The applicability of the method to the commercial production of drugs has not yet been demonstrated. Separately, it is necessary to evaluate the possibility of scaling the reaction and the properties of the obtained substances.

The new method gives researchers an additional way to change the molecular framework. The results for the vinpocetine derivative show why such changes are worth studying: replacing one atom can improve several laboratory characteristics. Whether these benefits will become the basis for a new drug should be determined by further testing.