This Review is a comprehensive overview on the most important aspects of fluorine substituents on the receptor binding of pharmaceuticals ("Fluorine in pharmaceuticals: Looking beyond intuition," by K. Mueller et al., 28 September 2007, p. 1881). Interestingly, however, an important class in which the effects of fluorination have long been investigated are not mentioned at all: corticosteroids, including gluco- and mineralocorticoids. The importance of these compounds is well-illustrated by the fact that glucocorticoid receptors (GR) are the target with the most number of drugs approved, together with the histamine H1 receptor (1). Halogenation (mostly fluorination) at 9α (and possibly at 6α) has been long known to enhance glucocorticoid activity (2, 3), and recent analysis of a large number of GR binding data (4) found that, after correctly taking into account nonspecific interactions related to ligand size, 6α- or 9α-halogenation causes, on average, a six- to seven-fold increase in binding (corresponding to ΔΔG0 = –4.7±0.4 kJ/mol = –1.1±0.1 kcal/mol). Remarkably, this is exactly the same effect seen for the H/F substitution by the authors in thrombin inhibitors. Intriguingly, however, the second fluorination or fluorination in a cyclic 16, 17-acetal containing steroid no longer increases GR binding significantly (4). Furthermore, whereas 6α fluorination seems to have about the same effect on GR binding as 9α fluorination (2, 4), it does not seem to have such an effect on mineralocorticoid activity (5) or on the binding of progesterone to its receptor (6, 7). On the basis of its magnitude, it is possible that this effect is hydrogen-bond related (4); however, available crystal structures for the human GR ligand-binding domain with dexamethasone (8, 9) do not indicate the presence of any special interactions at the 9α-F position. Only a phenyl moiety (Phe623) is closer than 4 Å, but hydrogen-bonding of the 11β-OH (with Asn564) might be enhanced due to electron-withdrawing effects.
Peter Buchwald
Director, Drug Discovery, Diabetes Research Institute, University of Miami, Miami, FL 33136, USA.
References
1. J. P. Overington, B. Al-Lazikani, A. L. Hopkins, Nat. Rev. Drug Discov. 5, 993 (2006).
2. M. E. Wolff et al., Biochemistry 17, 3201 (1978).
3. N. Bodor, A. J. Harget, E. W. Philips, J. Med. Chem. 26, 318 (1983).
4. P. Buchwald Steroids Epub, http://www.sciencedirect.com/science/journal/0039128X (doi:10.1016/j.steroids.2007.10.001) (2007).
5. J. W. Funder, W. R. Adam, F. Mantero, N. Kraft, S. Ulick, J. Clin. Endocrinol. Metab. 49, 842 (1979).
6. D. H. Seeley, W. Y. Wang, H. A. Salhanick, J. Biol. Chem. 257, 13359 (1982).
7. M. Issar, S. Sahasranaman, P. Buchwald, G. Hochhaus, Eur. Respir. J. 27, 511 (2006).
8. R. K. Bledsoe et al., Cell 110, 93 (2002).
9. B. Kauppi et al., J. Biol. Chem. 278, 22748 (2003).
E-Letters: ![[Read E-Letter]](/icons/misc/sectionDOWN.gif){kind=icon}
