Direct Enantiomer Differentiation of Drugs and Drug-Like Compounds via Noncovalent Copper–Amino Acid Complexation and Ion Mobility-Mass Spectrometry
Year: 2024
Type: article
Abstract: High Resolution Image Download MS PowerPoint Slide Drug enantiomers can possess vastly different pharmacological properties, yet they are identical in their chemical composition and structural connectivity. Thus, resolving enantiomers poses a great challenge in the field of separation science. Enantiomer separations necessitate interaction of the analyte with a chiral environment─in mass spectrometry-based analysis, a common approach is through a three-point interaction with a chiral selector commonly introduced during sample preparation. In select cases, the structural difference imparted through noncovalent complexation results in enantiomer-specific structural differences, facilitating measurement using a structurally selective analytical technique such as ion mobility-mass spectrometry (IM-MS). In this work, we investigate the direct IM-MS differentiation of chiral drug compounds using mononuclear copper complexes incorporating an amino acid chiral selector. A panel of 20 chiral drugs and drug-like compounds were investigated for separation, and four l -amino acids ( l -histidine, l -tryptophan, l -proline, and l -tyrosine) were evaluated as chiral selectors (CS) to provide the chiral environment necessary for differentiation. Enantiomer differentiation was achieved for four chiral molecule pairs ( R / S -thalidomide, R / S -baclofen, R / S -metoprolol, and d / l -panthenol) with two-peak resolution ( R p–p ) values ranging from 0.7 (>10% valley) to 1.5 (baseline separation). Calibration curves relating IM peak areas to enantiomeric concentrations enabled enantiomeric excess quantitation of racemic thalidomide and metoprolol with residuals of 5.7 and 2.5%, respectively. Theoretical models suggest that Cu II and l -histidine complexation around the analyte chiral center is important for gas-phase stereoselectivity. This study demonstrates the potential of combining enantioselective noncovalent copper complexation with structurally selective IM-MS for differentiating chiral drugs and drug-like compounds.
Source: Analytical Chemistry
Authors: Benjamin K. Blakley, Emanuel Zlibut, Rashi M. Gupta, Jody C. May, John A. McLean
Institutions: Vanderbilt University, Vanderbilt-Ingram Cancer Center
Language: English
Subfield: Spectroscopy
Field: Chemistry
Domain: Physical Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
OpenAlex ID: W4400982746