Organofluorine in Medical Chemistry

The discovery of fluorine by Henri Moissan in 1886 is a landmark in the history of chemistry. In the past six decades, fluorine chemistry has developed from a curiosity to a ubiquitously found discipline. Many recent advances in solid-state chemistry, polymer chemistry, coordination chemistry, main group element chemistry, and organometallic chemistry have relied on the physical and chemical properties of the most electronegative element, fluorine. Many fluorine compounds are used in various areas of daily life and industry. This attests to the interdisciplinary nature of research in fluorine chemistry.
Fluorine is the most electronegative element in the periodic table. When bound to carbon it forms the strongest bonds in organic chemistry and this makes fluorine substitution attractive for the development of pharmaceuticals and a wide range of speciality materials. Although highly polarised, the C–F bond gains stability from the resultant electrostatic attraction between the polarised Cδ+ and Fδ- atoms. This polarity suppresses lone pair donation from fluorine and in general fluorine is a weak coordinator. However, the C–F bond has interesting properties which can be understood either in terms of electrostatic/dipole interactions or by considering stereoelectronic interactions with neighbouring bonds or lone pairs.
This paper summarizes the fluorine atom and fluorine group in drug molecule design. Because of the special properties of bound C-F, it has become evident that fluorinated compounds have a remarkable record in medicinal chemistry and will play a continuing role in providing lead compounds for therapeutic applications.
Fluorine has a big influence on physicochemical and conformational properties. 1) Perturbation of pKa. The perturbation of pKa can strongly modify the binding affinity and the pharmacokinetic properties of a pharmaceutical agent. the strong electronegativity of fluorine has a great influence on the acid and alkalinity of the compound. 2) Modulation of lipophilicity. At the molecular level, when the fluorine atom or fluorine group to replace the hydrogen atoms, often lead to small molecules lipophilic changes. Lipophilicity is very important in drug absorption, distribution and drug-receptor interaction. The introduction of fluorine atoms enhances the membrane permeability of the drug molecule and forms a hydrophobic interaction with the specific site of the target protein. 3) Conformational changes. Fluorine substitution exerts only a minor steric demand at receptor sites. The introduction of a Fluorine group within a molecule may impose a drastic steric change. And strong electronic modification may also influence conformation. And the ability to bind the ligand to the target protein is altered by affecting the conformation. 4) Hydrogen bonding and electrostatic interactions. The importance of the carbon–fluorine bond in hydrogen bonding is still in contention. The C–F bond is highly nonpolarizable and can participate in weak hydrogen bonding only.
In addition, Fluorine also affects the metabolism of drugs. Metabolic stability is an important factor in determining the bioavailability of small molecules. The metabolic stability is a common problem in drug discovery process, and it is of great significance to improve the metabolic stability of small molecules. 1) Oxidative metabolism. In drug design, it’s a usual pathway to introduce the fluorine atoms to replace the oxidation of metabolic sites to protect, and selectively prevent the occurrence of oxidative metabolism, thereby enhancing the metabolic stability of the compound to extend the role of drugs in vivo time. 2) Hydrolytic metabolism. Hydrolytic stability can be greatly enhanced by fluorination. 3) In vivo racemization. Due to the particularity of the fluorine atom, it will have an effect on the optical properties of the drug in vivo metabolism.
Another major development in the field is the rapid improvement in imaging technology allowing broader availability of PET scanners for researchers, and a wider range of tracers. The onset of PET imaging in both diagnostics and as a pharmacological imaging tool may even alter the decision making processes in drug discovery.
Due to the major successes of fluorinated compounds in medicinal chemistry, it may be predicted that the number of fluorine containing drugs on the market will continue to increase. With the fluorine chemical synthesis method of maturation and the new fluorine chemical reagents continue to appear, fluoride in drug development prospects will be broader.
However, the fluorine atom is highly active, and it is difficult to control the reaction, especially when introducing fluorine atoms at a specific position. The selective introduction of fluorine atoms and fluorine-containing groups is a major challenge in the field of pharmaceutical chemistry research and production.
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Purser, S., Moore, P. R., Swallow, S., & Gouverneur, V. (2008). Fluorine in medicinal chemistry. Chemical Society Reviews, 37(2), 320-330.
O’Hagan, D. (2008). Understanding organofluorine chemistry. An introduction to the C–F bond. Chemical Society Reviews, 37(2), 308-319.