Structure elucidation of aplidine metabolites formed in vitro by human liver microsomes using triple quadrupole mass spectrometry

J Mass Spectrom. 2005 Jun;40(6):821-31. doi: 10.1002/jms.863.

Abstract

The cyclic depsipeptide aplidine is a new anti-cancer drug of marine origin. Four metabolites of this compound were found after incubation with pooled human microsomes using gradient high-performance liquid chromatography with ultraviolet detection. After chromatographic isolation, the metabolites have been identified using nano-electrospray triple quadrupole mass spectrometry. A highly specific sodium-ion interaction with the cyclic structure opens the depsipeptide ring, and cleavage of the amino acid residues gives sequence information when activated by collision-induced dissociation in the second quadrupole. The aplidine molecule could undergo the following metabolic reactions: hydroxylation at the isopropyl group (metabolites apli-h 1 and apli-h 2); C-dealkylation at the N(Me)-leucine group (metabolite apli-da); hydroxylation at the isopropyl group and C-dealkylation at the N(Me)-leucine group (metabolite apli-da/h), and C-demethylation at the threonine group (metabolite apli-dm). The identification of these metabolites formed in vitro may greatly aid the elucidation of the metabolic pathways of aplidine in humans.

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism*
  • Chromatography, High Pressure Liquid
  • Depsipeptides / chemistry
  • Depsipeptides / metabolism*
  • Female
  • Humans
  • Male
  • Microchemistry / methods
  • Microsomes, Liver / metabolism*
  • Molecular Structure
  • Nanotechnology
  • Peptides, Cyclic
  • Spectrometry, Mass, Electrospray Ionization / methods*

Substances

  • Antineoplastic Agents
  • Depsipeptides
  • Peptides, Cyclic
  • plitidepsin