title: Impact of stereospecific intramolecular hydrogen bonding on cell permeability and physicochemical properties.
abstract: 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.
authors: CVMD iMed, AstraZeneca R&D Mölndal , SE-431 83 Mölndal, Sweden.
authors: Björn
authors: B
authors: Over
authors: Patrick
authors: P
authors: McCarren
authors: Per
authors: P
authors: Artursson
authors: Michael
authors: M
authors: Foley
authors: Fabrizio
authors: F
authors: Giordanetto
authors: Gunnar
authors: G
authors: Grönberg
authors: Constanze
authors: C
authors: Hilgendorf
authors: Maurice D
authors: MD
authors: Lee
authors: Pär
authors: P
authors: Matsson
authors: Giovanni
authors: G
authors: Muncipinto
authors: Mélanie
authors: M
authors: Pellisson
authors: Matthew W D
authors: MW
authors: Perry
authors: Richard
authors: R
authors: Svensson
authors: Jeremy R
authors: JR
authors: Duvall
authors: Jan
authors: J
authors: Kihlberg
mesh_terms: D000465:Algorithms; D000818:Animals; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects*; D019295:Computational Biology; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008055:Lipids / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D054852:Small Molecule Libraries; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D008055:Lipids; D054852:Small Molecule Libraries