19F NMR-oriented Fragment Library

Organofluorine compounds, particularly heterocyclic ones, are known to be very attractive targets in medicinal chemistry, both from the theoretical and synthetical point of view. The introduction of fluorine into organic molecules often results in dramatic modification of their chemical and pharmaceutical properties. Due to their unique features and high physiological activity, fluorine-containing compounds have received much attention in the literature recently [1].

Identification of bioactive compounds from commercially available sources by NMR spectroscopy has become increasingly important. A promising methodology based on 19F NMR spectroscopy for screening of ligands that bind to proteines has been suggested as a valuable addition to existing NMR techniques, as it provides qualitative information about relative binding strengths and the presence of multiple binding sites, and so could be used for evaluation of chemical libraries in bioorganic and medicinal chemistry [2]. In contrast to the traditional 1H NMR spectroscopy, 19F NMR spectra have a much broader resonance area - 300 ppm vs. 15 ppm for proton NMR. At the same time, 19F NMR spectra are much simpler to interpret, as they usually contain only a limited number of signals. Therefore 19F NMR spectroscopy could become a simple and efficient way to monitor ligand-protein interactions in vitro. As there were no commercially available 19F NMR-oriented fragment libraries, we at ACB Blocks have decided to satisfy this unmet demand. The resulted library contains 207 small drug-like compounds, most of them fitting strict NMR-&-Ro3 fragment criteria. The basic properties of the library are listed below:

  1. All compounds are drug-like and privileged structures. The selection of such specific fragments was based on the methodology of identification of privileged substructures [1].
  2. The compounds are highly diverse (especially in the sense of "heterocyclic" diversity). Actually, each compound represents a unique cluster (set or sub-library) of similar substances available from new chemistry that can be explored in further experiments.
  3. All compounds satisfy Ro5 criteria, and the most of them satisfy Ro3 rules.
    • Compounds are small - MW < 400. (Ro3: MW < 330),  average MW = 300
    • Compounds typically have:
      • 1—3 rings (Ro3: not more 3);
      • 1—5 rotatable bonds (Ro3 < 6), average 2.72;
      • 1—3 donors of hydrogen bonds (Ro3 < 3), average 1.42;
      • 1—5 acceptors of hydrogen bonds (Ro3: minimum — 1, maximum — 6), average 4.36.
  4. Compounds are non-aggregative.
  5. Purity of fragments is more than 95% (LCMS, NMR).
  6. Compounds are non-reactive. About 100 special filters were applied for elimination of compounds with unwanted functionality (NO2, SH, hydrazones, epoxides, alkylating agents, Michael acceptors, redox, etc.)
  7. Compounds are polar and non-lipophylic. ClogP < 5.0 for all the selected compounds (average 2.49). These results are obtained with ALOGPC program [4, 5].
  8. Compounds should prove soluble in D2O. Solubility predicted with ALOGPC software seems very promising, as all compounds have ClogSW > -4.50 (average -3.46).
Molecular weight LogP LogSw

Molecular weight

LogP

LogSw

Number of rotatable bonds Number of hydrogen bond donors Number of hydrogen bond acceptors

Number of rotatable bonds

Number of hydrogen bond donors 

Number of hydrogen bond acceptors

We hope the proposed product becomes a powerful tool for NMR-based screening.

[1] Hudlicky M., Pavlath A.E. Chemistry of Organic Fluorine Compounds II. A Critical Review. ACS Symposium Series, Vol 187, American Chemical Society, Washington, 1995.

[2] Tengel T., Fex T., Emtenas H., Almqvist F., Sethson I., Kihlberg J. Use of 19F NMR spectroscopy to screen chemical libraries for ligands that bind to proteins. Org. Biomol. Chem. 2004, 2, 725-31.

[3] Baurin N., Aboul-Ela F., Barril X., Davis B., Drysdale M., Dymock B., Finch H., Fromont C., Richardson C., Simmonite H., Hubbard R.E. J. Chem. Inf. Comput. Sci. 2004, 44, 2157-2166.

[4] Tetko I., Bruneau P. J. Pharm. Sci. 2004. 93, 3103-3110.

[5] Tetko I., Poda G. J. Med. Chem. 2004, 47, 5601-5604.