Fluorine in pharmaceuticals

Among the lessons which I learnt in graduate school was another important one: organic fluorine rarely forms hydrogen bonds. The layman's explanation for this phenomenon is that F holds tightly on to its electrons and does not share them.

However, there are enough number of examples among protein-ligand interactions, although much fewer than the other ones, to warrant attention to the role of F in drugs. The review in the latest issue of Science does exactly that. (DOI: 10.1126/science.1131943)

Some of the salient points I got from this and other reviews:

1. F as bioisostere: As is known, because of its similar size, F can be a good bioisostere for O, and C-F bonds can stand in for C-O bonds. The review mentions C-CF3 as substitute for C-O, and vinyl C=C-F as substitute for peptide bonds. The introduction of F can considerably alter conformational preferences. The review mentions the interesting case of O-CH3 vs O-CF3 bonded to an aromatic ring. In the former, the group is in the plane of the ring because of pi-orbital conjugation with the ring, whereas in the latter, O-antibonding C-F orbital conjugation destroys this preference and swings the group orthogonal to the ring.

2. F as acidity promoter: It is well-known that F increases the acidity of amines. In some cases, one can decrease the pKa to below 7, so that the amines will not be protonated at physiological pH. This can have the consequence both of improving permeability by increasing the neutral form of the amine, and radically changing the binding mode. A remarkable example is of a series of thrombin inhibitors, where the pKa could be decreased from 10 to <2 by introducing well-positioned Fs. I have already talked about the exceptional case of 3-F piperidines.

3. F as lipophilicity enhancer: Another important property of increasing the logD value. The review also mentions cases where the logD actually falls. F's lipophilicity has been famously incorporated into Teflon®, and hexafluoroisopropanol and hexafluoroacetone are often used to enhance alpha-helical content of peptides on the basis of this property. Balaram and Rajan have argued that these solvents actually "dry" the peptides ("Teflon coated peptides")

4. F as H-bonder: A unique property of this chap. I always remember a review by Dunitz in which he statistically examined a large number of CSD entries and found an exceedingly small number of cases where organic F could be a bonafide H-bond acceptor. However, there are also cases, where F in ligands shows close proximity to C-H, N-H, and most interestingly, C=O bonds where F interacts with the carbonyl carbon. This is in contrast to the recently investigated "halogen bonds" where Br and Cl seem to interact with carbonyl oxygen in proteins.

Clearly, F's behaviour in enhancing protein-drug interactions is valuable. And it remains as interesting and enigmatic as ever. An always colorful beast.

Three lessons

When you have been in graduate school for two or three years, it's a good question to ask which are the important lessons you have learnt from your time there. These are not the "lessons of life" I am talking about- they are perhaps even more important- but technical lessons which spring to your mind. In my case, three lessons strikingly come to my mind. All of them are related to work that our group has done, but also to other people's work and general thought. All of them deal with material published in the literature that is unfortunately "fiction", and articles in journals don't seem to acknowledge this fact. Here they are:

1. Oxidation states for transition metals greater than 1 (eg. Au3+, Cu2+) are fictional and non-existent (related post and references)
2. Single "average" structures derived from NMR for flexible molecules are fictional and "virtual" (related post and references)
3. 3-fluoropiperidines exist in solution almost exclusively as the axial-F conformer. (related post and references)

Pretty basic stuff

One of the more enlightening facts about conformational analysis I learnt in the last couple of years was related to the simple question, "What is the proportion of the axial conformer in 3-fluoro piperidine?" Contrary to what most of our knowledge about six membered ring conformational analysis says, the answer is:

100%. The axial conformer is present to the extent of 100%. The equatorial- 0%



The situation arises because of a stabilizing C-F...N-H+ dipole effect that also raises the pKa of this molecule over what we would assume. This analysis was done in a series of papers by Lankin, Snyder et al.

This study is part of a recent ChemMedChem review that tackles the wide range of amine basicities in drug like molecules, and the factors that influence them. I have now learnt to mentally protonate requisite nitrogens when I see them in a drug almost as a reflex action, but I still get a little bamboozled sometimes. While the influence of inductive and polar effects on the lowering of amine pKas is well known, effects like the one noted above are more subtle and unexpected and such trends are discussed in the review.

For example, the above 1,3 syn kind of fluorine-amine interaction also extends to acyclic systems, and nicely explains the simple differences in basicities of the simplest of compounds; mono, di, and trifluoro ethyl amines (pKas drop down from around 10-11).



One of those set of principles well kept in mind