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

Molecules

卷:26

Ji-Yoon Lee¹  SooJin Oh¹  JungAh Kim²  DongGu Yoo²  EunJin Shin²  Kyeong Lee³  Kiho Lee⁴  Cho-Rock Jung⁵  MinJu Kim⁶ 

[1] Asan Medical Center, Asan Institute for Life Sciences, Seoul 05505, Korea;

[2] Asan Medical Center, Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, University of Ulsan College of Medicine, Seoul 05505, Korea;

[3] BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea;

[4] Department of Pharmacy, College of Pharmacy, Korea University, Sejong 30019, Korea;

[5] Gene Therapy Unit, KRIBB, Daejeon 34141, Korea;

[6] Laboratory Animal Resource Center, KRIBB, Chungbuk 28116, Korea;

关键词: LW6;    hypoxia-inducible factor-1α;    metabolite identification;    hybrid triple quadrupole-linear ion trap mass spectrometer;    predictive multiple reaction monitoring-information dependent acquisition-enhanced product ion;   

DOI  :  10.3390/molecules26071951

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown