Details

Autor(en) / Beteiligte

• Over, Björn
• McCarren, Patrick
• Artursson, Per
• Foley, Michael
• Giordanetto, Fabrizio
• Grönberg, Gunnar
• Hilgendorf, Constanze
• Lee, Maurice D
• Matsson, Pär
• Muncipinto, Giovanni
• Pellisson, Mélanie
• Perry, Matthew W. D
• Svensson, Richard
• Duvall, Jeremy R
• Kihlberg, Jan

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2014-03, Vol.57 (6), p.2746-2754

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2014

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Profiling of eight stereoisomeric T. cruzi growth inhibitors revealed vastly different in vitro properties such as solubility, lipophilicity, pK a, 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 pK a 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.