Supporting Online Material for

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1 Supporting Online Material for Fluorine in Pharmaceuticals: Looking Beyond Intuition Klaus Müller,* Christoph Faeh, François Diederich* *To whom correspondence should be addressed. (K.M.); (F.D.) This PDF file includes: Figs. S1 to S5 Tables S1 and S2 References Published 28 September 2007, Science 317, 1881 (2007) DOI: /science

2 Fig. S1. Left: A search in the CSD reveals occurrences for aryl OCH 3 : most of the structures show the O C(H 3 ) bond in plane with the aromatic ring. N is the number of occurrences found, θ is the dihedral angle C aryl C aryl O CX 3 (X: H or F). Right: A search in the CSD reveals 13 occurrences for aryl OCF 3, demonstrating a preference for the O C(F 3 ) bond to orient orthogonally with respect to the aromatic ring. Both searches were done with at least one hydrogen substituent in the ortho position relative to the OCX 3 (X = H, F) residue.

3 Fig. S2. Fluorination of propylbenzene leads to a decrease in logp. The measured values (S1) can be rationalized assuming an essentially similar polarity increase due to local dipole moments for the CH 2 F and CF 3 groups (as plausible from the experimental gasphase dipole moments of simple fluorinated methane derivatives (S2), see lower part of the Figure) and a logp increase proportional to the van der Waals volume change (van der Waals radius of fluorine taken as 1.47 Å (S3)). Based on the simple scheme above, the logp increase for V CH3/CF3 can be estimated as +0.5 corresponding to the typical logp change upon introduction of a CH 3 group, which is consistent with the fact that a CF 3 group occupies about double the van der Waals volume of a methyl group (see Table S2).

4 Fig. S3. A dramatic change in the conformation and orientation of the thrombin inhibitor is found when hydrogen (left) is replaced by a fluorine atom (right) (Table S1 entries 22, 23).

5 Fig. S4. An early example for orthogonal dipolar C F C=O interactions is provided by a p38 MAP kinase inhibitor which undergoes two such interactions with the protein (Table S1 entry 28).

6 Fig. S5. Two PDB searches investigate the interaction of ligand C F bonds with guanidinium side chains of Arg residues of proteins. Left: The search parameters d 1, d Å yielded 48 hits. Right: With the search parameter set to d 3 3.8, 32 hits were found.

7 Table S1. Crystal structures of protein-ligand complexes and small molecules discussed in the main text together with PDB code and reference. Entry Protein-ligand complex/ PDB-code/ Reference Small molecule crystal structure CSD-code 1 Fluoxetine FUDCOW S4 2 HMG-CoA reductase 1HWK S5 3 Acriflavine resistance protein B 1T9U S6 4 HIV-1 protease 1DIF S7 5 o-difluoromethoxybenzylideniminoxysilatrane VOQQEX S8 6 Human phosphodiesterase 4D 1XMU S9 7 Human phosphodiesterase 4D 1XOQ S9 8 Human phosphodiesterase 4D 1XOR S9 9 Human phosphodiesterase 4D 2FM0 S10 10 Human phosphodiesterase 4D 2FM5 S10 11 Human phosphodiesterase 4D 1MKD S11 12 Bovine trypsin 1O3M S12 13 Bovine trypsin 1O3N S12 14 Bovine trypsin 1O3O S12 15 Human dihydroorotate dehydrogenase 2BXV S13 16 Human dihydroorotate dehydrogenase 2FPT S13 17 Human dihydroorotate dehydrogenase 2FPY S13 18 Human dihydroorotate dehydrogenase 2FQI S13 19 Human cathepsin S 2HH5 S14 20 (R)-N-(3,4,5-trimethoxyphenyl)-N- ICENEJ S15 [[3-(trifluoromethylthio)phenyl]methyl] -N-(3,3,3-trifluoro-2-hydroxypropyl)amine hemihydrate 21 Human thrombin 2V3H S16 22 Human thrombin 2V3O S16 23 Human thrombin 1OYT S17 24 Porcine pancreatic elastase 2EST S18 25 Endoglucanase 5A 1H2J S19 26 Metalloprotease stromelysin 1USN S20 27 Carbonic anhydrase II 1G54 S21 28 p38 MAP kinase 1BL7 S22

8 Table S2: Van der Waals radii of atoms, bond lengths and total extensions, and van der Waals volume of substituents. Van der Waals radius Fluorine 1.35 Å 1.47 Å S23 S3 Hydrogen 1.20 Å S23, S3 Oxygen 1.40 Å 1.52 Å S23 S3 Bond length C F 1.35 Å 1.41 Å S24 S25 C H 1.09 Å S24 C O 1.43 Å S25 Total exensions C F 2.82 Å S25 C=O 2.72 S25 Van der Waals volume CF Å3 S26 CH Å3 S26 ((CH3)2CH 56.2 Å3 S26 CH3CH Å3 S26

9 References S1. MedChem database version 06, Daylight Chemical Information Systems, Inc., Aliso Viejo, CA 92656, USA. S2. R. C. Weast, Handbook of Chemistry and Physics, (CRC Press, Inc., Cleveland, Ohio, ed. 58, 1977). S3. A. Bondi, J. Phys. Chem. 68, (1964). S4. D. W. Robertson, N. D. Jones, J. K. Swartzendruber, K.S.Yang, D.T. Wong, J. Med. Chem. 31, (1988). S5. E. S. Istvan, J. Deisenhofer, Science 292, (2001). S6. E. W. Yu, J. R. Aires, G. McDermott, H. Nikaido, J. Bacteriol. 187, (2005). S7. A. M. Silva, R. E. Cachau, H. L. Sham, J. W. Erickson, J. Mol. Biol. 255, (1996). S8. E. Lukevics, L. Ignatovich, L. Golomba, J. Popelis, S. Belyakov, Main Group Met. Chem. 23, (2000). S9. G. L. Card et al., Structure 12, (2004). S10. Q. Huai et al., J. Med. Chem. 49, (2006). S11 M. E. Lee, J. Markowitz, J.-O. Lee, H. Lee, FEBS Lett. 530, (2002). S12. B. A. Katz et al., J. Mol. Biol. 329, (2003). S13. R. Baumgartner et al., J. Med. Chem. 49, (2006). S14. D. C. Tully et al., Bioorg. Med. Chem. Lett. 16, (2006). S15. R. C. Durley et al., J. Med. Chem. 43, (2000). S16. D. Banner, structures released for PDB publication. S17. J. A. Olsen et al., Angew. Chem. Int. Ed. 42, (2003). S18. D. H. Hughes, L. C. Sieker, J. Bieth, J.-L. Dimicoli, J. Mol. Biol. 162, (1982). S19. A. Varrot, G. J. Davies, Acta Crystallogr. D59, (2003). S20. B. C. Finzel et al., Protein Sci. 7, (1998). S21. C.-Y. Kim et al., J. Am. Chem. Soc. 122, (2000).

10 S22 Z. Wang et al., Structure 6, (1998). S23. L. Pauling, The Nature of the Chemical Bond (Cornell University Press, Ithaca, New York, ed. 6, 1948). S24. D. R. Lide et al., CRC Handbook of Chemistry and Physics (CRC Press, Boca Raton, ed. 86, 2005). S25. J. C. Biffinger, H. W. Kim, S. G. DiMagno, ChemBioChem 5, (2004). S26. F. Leroux, ChemBioChem 5, (2004).