Fluorine brings new drugs to fruition

Fluorine is an increasingly common ingredient in medicines. Joel Swinson of Halocarbon Products Corporation explains why it has become a useful addition to the developer's toolbox.

Nature makes huge numbers of chemically diverse complex molecules, many of which have biological activity.Bacteria in particular are a rich source of medicinally useful compounds, as they biosynthesise a whole host of chemicals that have an effect in the human body, or kill the organisms that infect it. However, very few of the active organic compounds created by bacteria contain fluorine atoms, even though around a fifth of all pharmaceutical products on the market contain at least one fluorine moiety.

A major reason for the paucity of naturally-occurring fluorinated compounds is the low concentration of free fluoride ions in the environment compared with chloride. As a result, bacteria have evolved to incorporate what is available to them, hence the higher number of natural products that contain chlorine atoms. In addition, the redox potential of fluoride makes it difficult to oxidise, essentially ruling out the major route used by the bugs to incorporate chloride into compounds. Although a fluorinating bacterium, Streptomyces cattleya, has been discovered recently, it remains very much an exception.

biological activity

So why has something so rare in nature become so common in medicines? A fundamental strategy for medicinal chemists when inventing new drugs is to take a molecule, frequently from nature, and make modifications to its structure to alter its activity. Replacing hydrogen and other functional groups with fluorine can have a dramatic effect on biological activity. It is much more strongly electronegative than hydrogen, so swapping a fluorine atom for a hydrogen atom can be expected to exert a large electronic effect on neighbouring carbon centres, altering both the dipole moment and the pKa of the molecule. It can also have a knock-on effect on the stability and reactivity of other functional groups in the compound.

Fluorine's van der Waals radius of 1.35Ã… may appear significantly larger than that of hydrogen, 1.10Ã…, but studies have shown that, size-wise, fluorine is actually a good hydrogen mimic, adding only limited extra steric demand at receptor sites.¹ In addition, its bond length to carbon of 1.26-1.41Ã… is reasonably similar to that of a carbon-hydrogen bond, which is in the region of 1.08-1.10Ã…. Therefore, replacing hydrogen with fluorine gives little change in the overall steric bulk of the molecule.

Fluorine substitutions may greatly increase a molecule's lipophilicit; an important consideration when making molecules that are designed to be active in vivo. Incorporating fluorines increases fat solubility, improving its partitioning into membranes and hence increasing bioavailability. Fluorination can also aid hydrophobic interactions between the drug and binding sites on receptors or enzymes.

thermal stability

Carbon forms some of its strongest bonds with fluorine, with a higher oxidative and thermal stability than a carbon-hydrogen bond. The fluorine can also make reversible electrostatic bonds with some other functional groups. Despite the strength of the carbon-fluorine bond, however, as the conjugate base of a strong acid, fluoride is a good leaving group, and this can be factored into the design of drugs that are intended to form stable covalent bonds with their targets.

Introducing more than one fluorine atom at the same site can have more dramatic effects. Using difluoromethylene as a replacement for CH₂ has a substantial effect on both the physical properties and conformation of a molecule. It can also be considered as a replacement for oxygen, with the fluorines sitting in a similar position to the oxygen's lone pairs. It is a similar shape and retains oxygen's ability to hydrogen bond, but the resulting carbon-carbon bonds are much more difficult to break, imparting greater stability.

early use

One of the earliest synthetic fluorinated drugs was the antineoplastic agent 5-fluorouracil, which was first synthesised in 1957.² It shows high anticancer activity as it inhibits the enzyme thimidylate synthetase and stops the cellular synthesis of thymidine, unlike the analogous 5-bromo derivative, which, presumably, is too large to be used in the biosynthesis in place of uracil.

Since the advent of 5-fluorouracil, fluorine substitution has become a common strategy in the drug discovery process, whether by modifying natural molecules, as in the case of 5-fluorouracil, or as part of a systematic search for more active analogues of existing drugs. A good example of the latter is flunitrazepam (Rohypnol, Roche), which is more effective than its non-fluorine containing parent, nitrazepam (Mogadon, also Roche). The only structural difference between the two drugs is an ortho fluoro phenyl substituent.

It is hardly a surprise, therefore, that so many common drugs contain fluorine. This includes three of the top 10 best-selling drugs in 2003: the best seller, Pfizer's cholesterol lowering agent atorvastatin (Lipitor), has an aromatic fluorine substituent; the proton pump inhibitor lansoprazole (Prevacid) from TAP contains a difluoromethylene unit; and the fluticasone component in GlaxoSmithKline's combination asthma treatment Seretide has three separate aliphatic fluorine substituents.

Many other medicines also have fluorine functionality: the antidepressants fluoxetine (Prozac, Lilly) and fluvoxamine (Luvox, Solvay) both have para phenyl trifluoromethyl groups, while GlaxoSmithKline's Paxil (paroxetine) has a para phenyl fluoro substituent. AstraZeneca's anticholesterol drug rosuvastatin (Crestor), like the top seller atorvastatin, has an aromatic fluorine. Several antibacterials contain fluorine, including the penicillin derivative floxacillin and Bayer's big selling quinolone antibiotic ciprofloxacin (Cipro), both of which also have a fluorine substituent on a phenyl group. The antifungal fluconazole (Diflucan, Pfizer) has two aromatic fluorines, and the antimalarial drug mefloquine (Lariam, Roche) contains two trifluoromethyl groups attached to its quinoline core, one on each ring.

safer intermediates

Despite the startling number of pharmaceutical products that contain fluorine, selective fluorination reactions are rarely straightforward. They often use dangerous reagents such as elemental fluorine or hydrogen fluoride, which are best avoided in large scale synthetic procedures. Specialist fluorinating reagents such as SF4, TBAF, DAST, Selectfluor and Deoxo-Fluor are often expensive, and can be tricky to handle. Therefore, the best route is often to let someone else worry about introducing the fluorine, by using a commercially available intermediate that already contains the correct fluorinated functionality, and then building the drug molecule around that.

A good example is the range of trifluoromethyl intermediates produced by fluorochemical specialist Halocarbon, which have the potential to be used to introduce trifluoromethyl functionality into molecules. The reasons for using a CF3 unit in place of a methyl group are, again, based on the similar size of fluorine and hydrogen, and the significant difference in their electronic character. The degree of electronic change is much greater than in a simple fluorine for hydrogen switch, however, purely on account of the fact that three fluorines have been introduced into the system instead of just the one. In addition, the trifluoromethyl group is one of the most lipophilic groups known.

new drugs

Numerous drug molecules contain trifluoromethyl moieties. As well as those mentioned above, both of Pfizer's COX-2 inhibitor anti-arthritis drugs celecoxib (Celebrex) and valdecoxib (Bextra) contain a trifluoromethyl substituent attached to a heteroaromatic ring. And efavirenz (Sustiva) from Bristol-Myers Squibb, a non-nucleoside reverse transcriptase inhibitor used in the treatment of HIV patients, has a trifluoromethyl group attached to a tertiary centre in a heteroaliphatic ring.

The easiest way of making all three of these medicines relies on a small molecule intermediate that contains a trifluoromethyl unit to introduce the fluorine functionality. Numerous intermediates from Halocarbon have potential here. These include trifluoroacetic acid and its methyl and ethyl esters, plus trifluoroacetyl chloride, trifluoroethanol, and even hexafluoroisopropanol. Trifluoroacetone and trifluoroacetaldehyde ethyl hemiacetal can also be used in the production of pharmaceutical actives.

Fluorine's unique properties mean it will continue to be a common structural element in the medicines that reach the market in the future. Synthetic routes that incorporate fluorinated fragments are frequently the most cost-effective and safest way of making fluoro drugs, and the importance of fluoro intermediates is only going to increase in coming years as new fluorinated drugs are introduced.