Fluorination of Medicinal Compounds

Uracil and 5-fluorouracil

Uracil

The VDW radius of fluorine (1.35Å) is larger than that of hydrogen (1.10Å), but the fluorine atom is in fact not much larger than that of the hydrogen it has replaced. This means no extra steric demand is added onto the drug molecule and so steric interactions at drug receptor sites are largely unaffected.

The comparison also shows that there is a larger amount of electron density towards fluorine, so it can form strong covalent bonds. This can be useful for drug design.

(Red represents areas which are electron rich, blue represents areas that are electron poor)

5-fluorouracil

In the above example 5-fluorouracil acts as a transition state inhibitor and is an example of an isosteric replacement of hydrogen, 5-fluorouracil becomes covalently bound to an active site on thymidylate synthase due to the strength of the carbon to fluorine bond, which is not present in uracil alone. So, 5-fluorouracil can act as an anti-cancer agent.