Structural Characterization of Anticancer Drug Paclitaxel and Its Metabolites Using Ion Mobility Mass Spectrometry and Tandem Mass Spectrometry

Abstract

Paclitaxel (PTX) is a popular anticancer drug used in the treatment of various types of cancers. PTX is metabolized in the human liver by cytochrome P450 to two structural isomers, 3′-p-hydroxypaclitaxel (3p-OHP) and 6α-hydroxypaclitaxel (6α-OHP). Analyzing PTX and its two metabolites, 3p-OHP and 6α-OHP, is crucial for understanding general pharmacokinetics, drug activity, and drug resistance. In this study, electrospray ionization ion mobility mass spectrometry (ESI-IM-MS) and collision induced dissociation (CID) are utilized for the identification and characterization of PTX and its metabolites. Ion mobility distributions of 3p-OHP and 6α-OHP indicate that hydroxylation of PTX at different sites yields distinct gas phase structures. Addition of monovalent alkali metal and silver metal cations enhances the distinct dissociation patterns of these structural isomers. The differences observed in the CID patterns of metalated PTX and its two metabolites are investigated further by evaluating their gas-phase structures. Density functional theory calculations suggest that the observed structural changes and dissociation pathways are the result of the interactions between the metal cation and the hydroxyl substituents in PTX metabolites.

Automated and efficient quantum chemical determination and energetic ranking of molecular protonation sites

“…For taxol, two different protonation sites have been observed in an ESI‐IM‐MS experiment . The three protonation sites that were found by our GFN‐xTB LMO procedure are at the N1, O7, and O13 positions (the LMOs and the structures are shown in Fig.…”

“…In recent years, the terms protomer (isomers of protonated molecules) and catiomer (isomers of molecules with a positive molecular charge depending on the site of protonation) have appeared in the literature . Research has been conducted on the protomer equilibria for a wide range of molecules, from nicotine and its derivatives to peptides and drug molecules like taxol . Pagel, Bowers and coworkers have recently published two instructive papers on the protomers of aminobenzoic acids, which have also been investigated by Cismesia and coworkers .…”

Adding a new separation dimension to MS and LC–MS: What is the utility of ion mobility spectrometry?

“…Lee et al. investigated metabolites of the anticancer drug Paclitaxel to study hydroxylation at different sites using TWIMS–MS and supported their results with theoretical calculations . Beucher et al.…”

“…7) [112]. Lee et al investigated metabolites of the anticancer drug Paclitaxel to study hydroxylation at different sites using TWIMS-MS and supported their results with theoretical calculations [113]. Beucher et al studied nonsteroidal selective androgen receptor modulators, which are prohibited by the World Anti-Doping Agency, but remain readily available and potentially used in livestock production for growth promotion [114].…”