(S)-1-(1-Methylpyridin-2-yl)-3-aminopiperidine as a novel derivatization reagent capable of enantiomeric separation and enhanced ESI-MS/MS detection for chiral carboxylic acids

Takaaki Matsumoto, Maho Sato, Wataru Yamazaki, Shoujiro Ogawa, Tatsuya Higashi

Research output: Contribution to journalArticle

Abstract

A novel derivatization reagent, (S)-1-(1-methylpyridin-2-yl)-3-aminopiperidine (MPAPp), was designed and developed for the enantiomeric separation by conventional reversed-phase liquid chromatography (LC) and the sensitive electrospray ionization-tandem mass spectrometry (ESI-MS/MS) detection of chiral carboxylic acids. MPAPp reacted with the carboxylic acids at 60 °C within 5 min in the presence of a condensation agent to produce the positively-charged and diastereomeric derivatives. The MPAPp-derivatization enabled the satisfactory enantiomeric separation not only of the α- and β-chiral carboxylic acids [ketoprofen (KET), etodolac and 3-hydroxypalmitic acid], but also of the γ-chiral carboxylic acid [2-(γ-carboxyethyl)-6-hydroxy-2,7,8-trimethylchroman (γ-CEHC)] with the resolution (Rs) values of 1.35–1.82. The derivatization also worked for the enantiomeric separation of the ε-chiral carboxylic acid [α-lipoic acid, separation factor (α) = 1.04]. The detection responses of the MPAPp-derivatives were 25–500-times greater than the intact carboxylic acids, therefore, the low femtomolar derivatives were fully detected. The trace detection of a γ-CEHC enantiomer (limit of detection, 1.9 fmol on column) in saliva was achieved by the MPAPp-derivatization followed by LC/ESI-MS/MS. The pharmacokinetic profiles of the KET enantiomers during/after the MOHRUS® patch application were also obtained from the saliva analysis using the MPAPp-derivatization based LC/ESI-MS/MS method, which was precise (intra- and inter-assay relative standard deviations, <6.6% and <4.6%, respectively) and accurate (96.2–105.3%) within the range of 35–280 pg/mL for each enantiomer.

Original languageEnglish
Pages (from-to)25-33
Number of pages9
JournalMicrochemical Journal
Volume146
DOIs
Publication statusPublished - 1 May 2019

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Carboxylic Acids
Enantiomers
Liquid chromatography
Ketoprofen
Derivatives
Assays
Etodolac
Thioctic Acid
Electrospray ionization
Pharmacokinetics
Mass spectrometry
Condensation

Keywords

  • Chiral carboxylic acid
  • Derivatization reagent
  • Enantiomeric separation
  • Enhanced sensitivity
  • LC/ESI-MS/MS

Cite this

@article{b0af62d228014bdbba6227e4183fb9e7,
title = "(S)-1-(1-Methylpyridin-2-yl)-3-aminopiperidine as a novel derivatization reagent capable of enantiomeric separation and enhanced ESI-MS/MS detection for chiral carboxylic acids",
abstract = "A novel derivatization reagent, (S)-1-(1-methylpyridin-2-yl)-3-aminopiperidine (MPAPp), was designed and developed for the enantiomeric separation by conventional reversed-phase liquid chromatography (LC) and the sensitive electrospray ionization-tandem mass spectrometry (ESI-MS/MS) detection of chiral carboxylic acids. MPAPp reacted with the carboxylic acids at 60 °C within 5 min in the presence of a condensation agent to produce the positively-charged and diastereomeric derivatives. The MPAPp-derivatization enabled the satisfactory enantiomeric separation not only of the α- and β-chiral carboxylic acids [ketoprofen (KET), etodolac and 3-hydroxypalmitic acid], but also of the γ-chiral carboxylic acid [2-(γ-carboxyethyl)-6-hydroxy-2,7,8-trimethylchroman (γ-CEHC)] with the resolution (Rs) values of 1.35–1.82. The derivatization also worked for the enantiomeric separation of the ε-chiral carboxylic acid [α-lipoic acid, separation factor (α) = 1.04]. The detection responses of the MPAPp-derivatives were 25–500-times greater than the intact carboxylic acids, therefore, the low femtomolar derivatives were fully detected. The trace detection of a γ-CEHC enantiomer (limit of detection, 1.9 fmol on column) in saliva was achieved by the MPAPp-derivatization followed by LC/ESI-MS/MS. The pharmacokinetic profiles of the KET enantiomers during/after the MOHRUS{\circledR} patch application were also obtained from the saliva analysis using the MPAPp-derivatization based LC/ESI-MS/MS method, which was precise (intra- and inter-assay relative standard deviations, <6.6{\%} and <4.6{\%}, respectively) and accurate (96.2–105.3{\%}) within the range of 35–280 pg/mL for each enantiomer.",
keywords = "Chiral carboxylic acid, Derivatization reagent, Enantiomeric separation, Enhanced sensitivity, LC/ESI-MS/MS",
author = "Takaaki Matsumoto and Maho Sato and Wataru Yamazaki and Shoujiro Ogawa and Tatsuya Higashi",
year = "2019",
month = "5",
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language = "English",
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T1 - (S)-1-(1-Methylpyridin-2-yl)-3-aminopiperidine as a novel derivatization reagent capable of enantiomeric separation and enhanced ESI-MS/MS detection for chiral carboxylic acids

AU - Matsumoto, Takaaki

AU - Sato, Maho

AU - Yamazaki, Wataru

AU - Ogawa, Shoujiro

AU - Higashi, Tatsuya

PY - 2019/5/1

Y1 - 2019/5/1

N2 - A novel derivatization reagent, (S)-1-(1-methylpyridin-2-yl)-3-aminopiperidine (MPAPp), was designed and developed for the enantiomeric separation by conventional reversed-phase liquid chromatography (LC) and the sensitive electrospray ionization-tandem mass spectrometry (ESI-MS/MS) detection of chiral carboxylic acids. MPAPp reacted with the carboxylic acids at 60 °C within 5 min in the presence of a condensation agent to produce the positively-charged and diastereomeric derivatives. The MPAPp-derivatization enabled the satisfactory enantiomeric separation not only of the α- and β-chiral carboxylic acids [ketoprofen (KET), etodolac and 3-hydroxypalmitic acid], but also of the γ-chiral carboxylic acid [2-(γ-carboxyethyl)-6-hydroxy-2,7,8-trimethylchroman (γ-CEHC)] with the resolution (Rs) values of 1.35–1.82. The derivatization also worked for the enantiomeric separation of the ε-chiral carboxylic acid [α-lipoic acid, separation factor (α) = 1.04]. The detection responses of the MPAPp-derivatives were 25–500-times greater than the intact carboxylic acids, therefore, the low femtomolar derivatives were fully detected. The trace detection of a γ-CEHC enantiomer (limit of detection, 1.9 fmol on column) in saliva was achieved by the MPAPp-derivatization followed by LC/ESI-MS/MS. The pharmacokinetic profiles of the KET enantiomers during/after the MOHRUS® patch application were also obtained from the saliva analysis using the MPAPp-derivatization based LC/ESI-MS/MS method, which was precise (intra- and inter-assay relative standard deviations, <6.6% and <4.6%, respectively) and accurate (96.2–105.3%) within the range of 35–280 pg/mL for each enantiomer.

AB - A novel derivatization reagent, (S)-1-(1-methylpyridin-2-yl)-3-aminopiperidine (MPAPp), was designed and developed for the enantiomeric separation by conventional reversed-phase liquid chromatography (LC) and the sensitive electrospray ionization-tandem mass spectrometry (ESI-MS/MS) detection of chiral carboxylic acids. MPAPp reacted with the carboxylic acids at 60 °C within 5 min in the presence of a condensation agent to produce the positively-charged and diastereomeric derivatives. The MPAPp-derivatization enabled the satisfactory enantiomeric separation not only of the α- and β-chiral carboxylic acids [ketoprofen (KET), etodolac and 3-hydroxypalmitic acid], but also of the γ-chiral carboxylic acid [2-(γ-carboxyethyl)-6-hydroxy-2,7,8-trimethylchroman (γ-CEHC)] with the resolution (Rs) values of 1.35–1.82. The derivatization also worked for the enantiomeric separation of the ε-chiral carboxylic acid [α-lipoic acid, separation factor (α) = 1.04]. The detection responses of the MPAPp-derivatives were 25–500-times greater than the intact carboxylic acids, therefore, the low femtomolar derivatives were fully detected. The trace detection of a γ-CEHC enantiomer (limit of detection, 1.9 fmol on column) in saliva was achieved by the MPAPp-derivatization followed by LC/ESI-MS/MS. The pharmacokinetic profiles of the KET enantiomers during/after the MOHRUS® patch application were also obtained from the saliva analysis using the MPAPp-derivatization based LC/ESI-MS/MS method, which was precise (intra- and inter-assay relative standard deviations, <6.6% and <4.6%, respectively) and accurate (96.2–105.3%) within the range of 35–280 pg/mL for each enantiomer.

KW - Chiral carboxylic acid

KW - Derivatization reagent

KW - Enantiomeric separation

KW - Enhanced sensitivity

KW - LC/ESI-MS/MS

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