An innovative method for converting hydrogen atoms into fluorine atoms for the production of more effective drugs

Chemists have long reported a simple method for converting hydrogen atoms into fluorine atoms within important drug molecules. This new discovery enables the fine-tuning of existing, as well as future, drugs in order to improve their properties

[Translation by Dr. Nachmani Moshe]

Chemists have long reported a simple method for converting hydrogen atoms into fluorine atoms within important drug molecules. This new discovery enables the fine-tuning of existing, as well as future, drugs in order to improve their properties

Most of the medicinal substances used to treat diseases in humans are based on an organic substance, meaning that the active ingredient is a molecule consisting of carbon and hydrogen atoms. This property is common to all living substances, such as proteins, sugars, fats and DNA, which are all based on hydrocarbon skeletons, differing from each other only in the set of modifiers on them and the addition of other possible elements in a smaller amount (mainly oxygen, nitrogen, sulfur and phosphorus). "Our body is nothing but a vast collection of billions of carbon-based organic molecules," says Nuno Maulide, a professor at the University of Vienna. Thanks to this analogy, organic drugs are the most effective in terms of their interactions with the human body, for example, by binding to receptors that cause the activation or inhibition of a required process.

The design of a drug molecule that gives rise to specific interactions with a suitable structure is usually described by analogy with the idea of ​​a 'lock and key'. "The receptor (for example, an enzyme) has a unique structure ('lock') and therefore requires another unique structure that matches it ('key') so that both will respond accordingly. Due to the need for precise matching, the structural integrity of the drug compound is the basis for ensuring the beneficial medical activity of the substance," explains one of the researchers.

However, just as nutrients are broken down inside the body, drugs that enter the body (and are composed of the same essential ingredients, carbon, hydrogen, etc.) are also broken down by the same enzymes that break down our food components. “This type of cleaning mechanism is essential for our body in order to protect itself; Molecules that are not required and may be harmful must be broken down in the body immediately. "Unfortunately, this mechanism does not distinguish between a harmful substance and a beneficial substance, so the drugs will also undergo decomposition in it as soon as they enter the body," explains the lead researcher. This mechanism may change the structure of the drugs and therefore also eliminate their beneficial properties. "Large parts of this decomposition occur exactly at the junction between a carbon atom and hydrogen atoms (carbon-hydrogen bonds), which may break or change to create new compounds that can be removed from the body more quickly by the secretions. Structurally, carbon-hydrogen bonds are quite weak bonds, which means that oxidation may easily occur," explains researcher Brashi. "Ultimately, this is a race where you run away from the body's natural avoidance mechanism! The longer the beneficial drug is able to escape from this discharge mechanism, the more beneficial it will be in the body," explains the researcher.

Therefore, it is obvious that if it is possible to eliminate or strengthen the weak structural points of the drug molecules, then it will be possible to significantly increase their metabolic stability. Several years ago, chemists discovered that the strategic replacement of extremely weak carbon-hydrogen bonds with much stronger carbon-fluorine bonds may be a particularly useful approach in this direction. Although hydrogen and fluorine differ in a number of aspects, their size is quite similar, and the conversion of hydrogen in fluorine can therefore have minimal consequences regarding the structure required for medical activity. "Due to the different electronic properties, the placement of a fluorine atom in the original position of hydrogen may even improve and add interactions with the biological target, while increasing the required medical activity," adds the researcher.

While the introduction of a fluorine atom into the drug molecule can lead to beneficial results, the synthesis of such fluorine compounds is not easy at all. Most of the common methods for fluorination (introducing a fluorine atom into a compound) involve the use of extremely active, corrosive and sometimes even toxic reagents. These reagents are based on positively charged fluorine atoms (F⁺), which are much more expensive and challenging to handle than their cheap counterparts of the type of negatively charged fluorine atoms, fluoride anions (F^-), which can also be found in toothpastes.

The researchers have now discovered a selective and simple method for introducing fluorine atoms into organic molecules using commonly available fluoride anions. "Most chemists looked for a way to introduce fluorine atoms using positively charged organic molecules capable of reacting with a positive fluorine ion. We simply did the opposite: changing the polarity of the organic molecule so that we could use the same cheap fluoride found in toothpastes", enthuses the lead researcher. And more importantly, this approach utilizes cheap starting materials, is quite simple and gives rise to high utilization of the desired product within a short period of time.

In the published article describing the research, a number of fluorinated equivalents of common biologically active substances were easily synthesized, the most prominent among them being the drug Citalopram. "The parent molecule citalopram is a blockbuster antidepressant used in the treatment of clinical depression. It reacts with serotonin transporter (SERT) and causes an increase in the concentration of serotonin while alleviating the symptoms of depression," explains the researcher. The researchers were able to prove that the activity of the drug citalopram is maintained after the introduction of a fluorine atom. In particular, while the original activity is preserved (despite the change in chemical structure), other pharmacological properties, such as metabolic stability and bioavailability, are expected to be improved as a result of this fluorination. The researchers believe, therefore, that fluoro-citalopram may present a viable alternative to its non-fluorinated counterpart. "Developing a simple method to convert hydrogen atoms into fluorine atoms under such simple conditions is just the beginning. We can now imagine performing this conversion on a variety of other pharmaceuticals and examine the properties of the resulting histories. Since such a conversion is also applicable for the materials industry, then it is understandable why we are so excited about the results of our research", says the lead researcher. "Our research is an excellent example of the power of chemistry: in light of the fact that we are able to change the structure of the material at the molecular level with atomic precision, the doors are opened to new studies that would otherwise be closed to researchers," concludes the lead researcher.

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