Quantitative determination of a potent geranylgeranyl diphosphate synthase inhibitor using LC–MS/MS

Derivatization and application

Yashpal S. Chhonker, Staci L. Haney, Robert A. Matthiesen, David F. Wiemer, Sarah A Holstein, Daryl J Murry

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

An isomeric mixture of homogeranyl/homoneryl triazole bisphosphonates (VSW1198) has previously been shown to be a potent inhibitor of geranylgeranyl diphosphate (GGDP) synthase (GGDPS) and of therapeutic interest for the treatment of multiple myeloma. We have developed and validated a selective and sensitive liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS) method for the simultaneous quantitation of both the E- and Z- isomers of VSW1198 in cell culture media, mouse plasma and tissues. VSW1198 and internal standard are extracted from the bio-matrices by solid-phase extraction, followed by derivatization using trimethylsilyldiazomethane. The chromatographic separation of analytes was achieved on a Phenomenex Gemini NX column (150 mm * 2.0 mm, 5 μ) with gradient elution using 0.1% acetic acid and methanol/acetonitrile (1:1) as the mobile phase at a flow rate of 0.2 mL/min. Derivatized analytes were ionized with an electrospray ionization source in positive multiple reaction monitoring (MRM) mode and quantitated using MS/MS. The MS/MS response was linear over the concentration range from 0.38–1500 and 0.13–500 ng/mL for the E- and Z-isomers, respectively. The within- and between-day precision (relative standard deviation, % RSD) and accuracy were within the acceptable limits per FDA guidelines. The validated method was used for quantitative determination of the compounds in preclinical studies focused on the development of VSW1198 as a novel anti-cancer agent.

Original languageEnglish (US)
Pages (from-to)22-28
Number of pages7
JournalJournal of Pharmaceutical and Biomedical Analysis
Volume153
DOIs
StatePublished - May 10 2018

Fingerprint

Farnesyltranstransferase
Isomers
Electrospray ionization
Triazoles
Solid Phase Extraction
Liquid chromatography
Diphosphonates
Ion sources
Tandem Mass Spectrometry
Multiple Myeloma
Cell culture
Liquid Chromatography
Acetic Acid
Mass spectrometry
Methanol
Culture Media
Cell Culture Techniques
Flow rate
Guidelines
Tissue

Keywords

  • Geranylgeranyl diphosphate synthase inhibitor
  • GGDP
  • GGPP
  • LC–MS/MS

ASJC Scopus subject areas

  • Analytical Chemistry
  • Pharmaceutical Science
  • Drug Discovery
  • Spectroscopy
  • Clinical Biochemistry

Cite this

Quantitative determination of a potent geranylgeranyl diphosphate synthase inhibitor using LC–MS/MS : Derivatization and application. / Chhonker, Yashpal S.; Haney, Staci L.; Matthiesen, Robert A.; Wiemer, David F.; Holstein, Sarah A; Murry, Daryl J.

In: Journal of Pharmaceutical and Biomedical Analysis, Vol. 153, 10.05.2018, p. 22-28.

Research output: Contribution to journalArticle

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