title: Chiral separation of tedizolid using charge single isomer derivatives of cyclodextrins by capillary electrokinetic chromatography.
abstract: A method to enantioseparate tedizolid (TED), the second analogue after linezolid (LIN) in a truly new class of antibacterial agents, the oxazolidinones, was developed based on capillary electrokinetic chromatography using cyclodextrin as chiral pseudophase (CD-cEKC). The single isomer R-tedizolid possesses one chiral centre at C5 of the oxazolidinone ring, which is associated with the antibacterial activity of the drug. Tedizolid enantiomers are non-charged and therefore require the use of charged cyclodextrins (CCDs) as carrier hosts to achieve a velocity difference during migration. During method development, hydrophilic anionic single-isomer and moderately hydrophobic and hydrophobic cyclodextrins were tested, including heptakis-(2,3-dihydroxy-6-sulfo)-β-cyclodextrin (HS-β-CD), heptakis-(2,3-diacetyl-6-sulfo)-β-cyclodextrin (HDAS-β-CD), oktakis-(2,3-diacetyl-6-sulfo)-γ-cyclodextrin (ODAS-γ-CD) and heptakis-(2,3-dimethyl-6-sulfo)-β-cyclodextrin (HDMS-β-CD). Only CDs that have acetyl groups at the C2 and C3 positions with seven (HDAS-β-CD) or eight (ODAS-γ-CD) residues of glucopyranose units provided baseline separation of the tedizolid enantiomers with the addition of organic solvent. During the experiments, different organic solvents were tested, such as methanol, acetonitrile, tetrahydrofuran, which varied in their abilities to donate or accept protons. The best enantiomer separation results were obtained using the CD-cEKC method with 37.5mM HDAS-β-CD dissolved in 50mM formic buffer (pH 4.0) with the addition of acetonitrile (81.4:18.6, v/v) at 27ºC, normal polarity, and 12kV. Finally, the apparent binding constants for each enantiomer-HDAS-β-CD pair were calculated. Moreover, in order to evaluate the behaviour of TED and LIN enantiomers relative to chiral selector, enantioselective interactions towards the precursors of TED and LIN isomers were also investigated.
authors.affiliation: Department of Antibiotics and Microbiology, National Medicines Institute, Chełmska 30/34, 00-725 Warsaw, Poland. Electronic address: k.michalska@nil.gov.pl.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Michalska
authors.affiliation: Department of Antibiotics and Microbiology, National Medicines Institute, Chełmska 30/34, 00-725 Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Gruba
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Poznań University of Medical Sciences, Grunwaldzka 6, 60-780 Poznań, Poland.
authors.forename: Judyta
authors.initials: J
authors.lastname: Cielecka-Piontek
authors.affiliation: Nuclear Magnetic Resonance Laboratory, National Medicines Institute, Chełmska 30/34, 00-725 Warsaw, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Bednarek
mesh_terms: D003505:Cyclodextrins / Q000737:chemistry*; D019075:Electrophoresis, Capillary / Q000379:methods; D000069349:Linezolid / Q000031:analogs & derivatives* / Q000032:analysis*; D010755:Organophosphates / Q000032:analysis* / Q000737:chemistry*; D010080:Oxazoles / Q000032:analysis* / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D003505:Cyclodextrins; D010755:Organophosphates; D010080:Oxazoles; D000069349:Linezolid; C515040:tedizolid phosphate
keywords: Antibacterial agent; CD-cEKC; Cyclodextrin; Enantioseparation; Synthesis; Tedizolid