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Title 

Synthesis and structure-activity relationship study of chemical probes as hypoxia induced factor-1α/malate dehydrogenase 2 inhibitors

 

HIF-1/MDH2 저해제로서 화학 프로브의 합성 및 활성 구조 상관관계

Authors 

R NaikMi Sun WonHyun Seung BanD BhattaraiX XuY EoYe Seul HongS SinghY ChoiH C AhnK Lee

Publisher 

American Chemical Society

Issue Date 

2014

Citation 

Journal of Medicinal Chemistry, vol. 57, no. 22, pp. 9522-9538

Abstract 

A structure-activity relationship study of hypoxia inducible factor-1α inhibitor 3-aminobenzoic acid-based chemical probes, which were previously identified to bind to mitochondrial malate dehydrogenase 2, was performed to provide a better understanding of the pharmacological effects of LW6 and its relation to hypoxia inducible factor-1α (HIF-1α) and malate dehydrogenase 2 (MDH2). A variety of multifunctional probes including the benzophenone or the trifluoromethyl diazirine for photoaffinity labeling and click reaction were prepared and evaluated for their biological activity using a cell-based HRE-luciferase assay as well as a MDH2 assay in human colorectal cancer HCT116 cells. Among them, the diazirine probe 4a showed strong inhibitory activity against both HIF-1α and MDH2. Significantly, the inhibitory effect of the probes on HIF-1α activity was consistent with that of the MDH2 enzyme assay, which was further confirmed by the effect on in vitro binding activity to recombinant human MDH2, oxygen consumption, ATP production, and AMP activated protein kinase (AMPK) activation. Competitive binding modes of LW6 and probe 4a to MDH2 were also demonstrated.

ISSN 

0022-2623

Link 

http://dx.doi.org/10.1021/jm501241g

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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