Metabolite Profiling and Characterization of LW6, a Novel HIF-1α Inhibitor, as an Antitumor Drug Candidate in Mice

A novel HIF (hypoxia-inducible factor)-1α inhibitor, the (aryloxyacetylamino)benzoic acid derivative LW6, is an anticancer agent that inhibits the accumulation of HIF-1α. The aim of this study was to characterize and determine the structures of the metabolites of LW6 in ICR mice. Metabolite identifi...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2021-03, Vol.26 (7), p.1951
Main Authors: Lee, Kiho, Lee, Ji-Yoon, Lee, Kyeong, Jung, Cho-Rock, Kim, Min Ju, Kim, Jung Ah, Yoo, Dong Gu, Shin, Eun Jin, Oh, Soo Jin
Format: Article
Language:English
Subjects:
Acetic acid
Benzoic acid
Biotransformation
hybrid triple quadrupole-linear ion trap mass spectrometer
Hydrolysis
Hypoxia
Hypoxia-inducible factor 1a
hypoxia-inducible factor-1α
Inhibitors
LW6
Metabolism
metabolite identification
Metabolites
Negative ions
Oxidation
Pharmacokinetics
Plasma
predictive multiple reaction monitoring-information dependent acquisition-enhanced product ion
Quadrupoles
Retention
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Summary:A novel HIF (hypoxia-inducible factor)-1α inhibitor, the (aryloxyacetylamino)benzoic acid derivative LW6, is an anticancer agent that inhibits the accumulation of HIF-1α. The aim of this study was to characterize and determine the structures of the metabolites of LW6 in ICR mice. Metabolite identification was performed using a predictive multiple reaction monitoring-information dependent acquisition-enhanced product ion (pMRM-IDA-EPI) method in negative ion mode on a hybrid triple quadrupole-linear ion trap mass spectrometer (QTRAP). A total of 12 metabolites were characterized based on their MS/MS spectra, and the retention times were compared with those of the parent compound. The metabolites were divided into five structural classes based on biotransformation reactions: amide hydrolysis, ester hydrolysis, mono-oxidation, glucuronidation, and a combination of these reactions. From this study, 2-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)acetic acid (APA, M7), the metabolite produced via amide hydrolysis, was found to be a major circulating metabolite of LW6 in mice. The results of this study can be used to improve the pharmacokinetic profile by lowering the clearance and increasing the exposure relative to LW6.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules26071951