Chiral separation of N-imidazole derivatives, aromatase inhibitors, by cyclodextrin-capillary zone electrophoresis. Mechanism of enantioselective recognition.
Baseline separation of ten new, substituted [1-(imidazo-1-yl)-1-phenylmethyl)] benzothiazolinone and benzoxazolinone derivatives with one chiral center was achieved using cyclodextrin-capillary zone electrophoresis (CD-CZE). A method for the enantiomeric resolution of these compounds was developed using neutral CDs (native alpha-, beta-, gamma-CDs or alpha-, beta-, gamma-hydroxypropyl (HP)-CDs) as chiral selectors. Operational parameters including the nature and concentration of the chiral selectors, pH, ionic strength, organic modifiers, temperature, and applied voltage were investigated. The use of neutral CDs provides enantiomeric resolution by inclusion of compounds in the CD cavity. The HP-alpha-CD and HP-beta-CD were found to be the most effective complexing agents and allowed efficient enantiomeric resolutions. Optimal separation of N-imidazole derivatives was obtained using 50 mM phosphate buffer at pH 2.5 containing either HP-alpha-CD or HP-beta-CD (7.5-12.5 mM) at 25 degrees C, with an applied field of 0.50 kV.cm(-1) giving resolution factors Rs superior to 1.70 with migration times of the second enantiomer less than 13 min. The same enantiomer migration order observed for all molecules can be related to a close interaction mechanism with CDs. The influence of structural features of the solutes on Rs and tm was studied. The lipophilic character (log kw) of the solutes and the apparent and averaged association constants of inclusion complexes for four compounds with the six different CDs led us to rationalize the enantioseparation mechanisms. The conclusions were corroborated with reversed-phase high-performance liquid chromatography (HPLC) on chiral stationary phases (CSPs) based on CDs.
Foulon
Catherine
C
Laboratoire de Chimie Analytique, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Lille, Lille, France.
Danel
Cécile
C
Vaccher
Marie-Pierre
MP
Bonte
Jean-Paul
JP
Vaccher
Claude
C
Goossens
Jean-François
JF
D047072:Aromatase Inhibitors / Q000737:chemistry* / Q000302:isolation & purification*; D002021:Buffers; D003505:Cyclodextrins; D019075:Electrophoresis, Capillary / Q000379:methods*; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000737:chemistry* / Q000302:isolation & purification*; D015394:Molecular Structure; D009994:Osmolar Concentration; D013237:Stereoisomerism; D013696:Temperature
D047072:Aromatase Inhibitors; D002021:Buffers; D003505:Cyclodextrins; D007093:Imidazoles