TY - JOUR
T1 - Metabolite profiling and characterization of LW6, a novel HIF-1α inhibitor, as an antitumor drug candidate in mice
AU - Lee, Kiho
AU - Lee, Ji Yoon
AU - Lee, Kyeong
AU - Jung, Cho Rock
AU - Kim, Min Ju
AU - Kim, Jung Ah
AU - Yoo, Dong Gu
AU - Shin, Eun Jin
AU - Oh, Soo Jin
N1 - Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/4/1
Y1 - 2021/4/1
N2 - 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.
AB - 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.
KW - Hybrid triple quadrupolelinear ion trap mass spectrometer
KW - Hypoxia-inducible factor-1α
KW - LW6
KW - Metabolite identification
KW - Predictive multiple reaction monitoring-information dependent acquisition-enhanced production
UR - http://www.scopus.com/inward/record.url?scp=85103920524&partnerID=8YFLogxK
U2 - 10.3390/molecules26071951
DO - 10.3390/molecules26071951
M3 - Article
C2 - 33808438
AN - SCOPUS:85103920524
SN - 1420-3049
VL - 26
JO - Molecules
JF - Molecules
IS - 7
M1 - 1951
ER -