title: A new quaternary ammonium cysteine analogue as a trapping reagent for reactive metabolites screening.
abstract: The novel cysteine-cholamine (Cys-chol) trapping reagent was synthesized by coupling N-(tertbutoxycarbonyl)- S-trityl-L-cysteine with cholamine in the presence of HBTU (O-(benzotriazol-1-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate), and then deprotecting by trifluoroacetic acid. Cys-chol reagent enhanced the sensitivity of reactive metabolite screening 4 to 20 times without introducing additional sample preparation or derivatization steps. Retention of Cys-chol conjugates on reversed-phase column is higher than for respective GSH conjugates which helps in reduction of background interference. The use of Cys-chol trapping reagent can potentially improve sensitivity and specificity of routine reactive metabolite screening assay in drug discovery.
authors.forename: Natalia
authors.initials: N
authors.lastname: Penner
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Drug Metabolism and Pharmacokinetics, Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA. natasha.penner@biogenidec.com.
authors.forename: Chandra
authors.initials: C
authors.lastname: Prakash
mesh_terms: D001711:Biotransformation; D002853:Chromatography, Liquid; D003024:Clozapine / Q000737:chemistry / Q000378:metabolism*; D003545:Cysteine / Q000031:analogs & derivatives / Q000138:chemical synthesis*; D055808:Drug Discovery / Q000379:methods*; D005978:Glutathione / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology*; D053719:Tandem Mass Spectrometry; D050337:Trimethyl Ammonium Compounds / Q000138:chemical synthesis*
chemical_list: D050337:Trimethyl Ammonium Compounds; C522723:cholamine; D005978:Glutathione; D003024:Clozapine; D003545:Cysteine