Impact of Stereospecific Intramolecular Hydrogen Bonding on Cell Permeability and Physicochemical Properties

• DOI: 10.1021/jm500059t
• Publication Date: 2014-02-13T17:06:03Z
• Authors: Björn Over; Patrick McCarren; Per Artursson; Michael Foley; Fabrizio Giordanetto; Gunnar Grönberg; Constanze Hilgendorf; Maurice D. Lee; Pär Matsson; Giovanni Muncipinto; Mélanie Pellisson; Matthew W. D. Perry; Richard Svensson; Jeremy R. Duvall; Jan Kihlberg
• Keywords: Models, Molecular; 0303 health sciences; Cell Membrane Permeability; Magnetic Resonance Spectroscopy; Trypanosoma cruzi; Molecular Conformation; Computational Biology; Hydrogen Bonding; Stereoisomerism; Hydrogen-Ion Concentration; Lipids; Small Molecule Libraries; Kinetics; Structure-Activity Relationship; 03 medical and health sciences; Solubility; Drug Design; Animals; Humans; Caco-2 Cells; Algorithms

Profiling of eight stereoisomeric T. cruzi growth inhibitors revealed vastly different in vitro properties such as solubility, lipophilicity, pKa, and cell permeability for two sets of four stereoisomers. Using computational chemistry and NMR spectroscopy, we identified the formation of an intramolecular NH→NR3 hydrogen bond in the set of stereoisomers displaying lower solubility, higher lipophilicity, and higher cell permeability. The intramolecular hydrogen bond resulted in a significant pKa difference that accounts for the other structure-property relationships. Application of this knowledge could be of particular value to maintain the delicate balance of size, solubility, and lipophilicity required for cell penetration and oral administration for chemical probes or therapeutics with properties at, or beyond, Lipinski's rule of 5.