Synthesis and Structure–Activity Relationship Study of Chemical Probes as Hypoxia Induced Factor-1α/Malate Dehydrogenase 2 Inhibitors

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2014-11, Vol.57 (22), p.9522-9538
Main Authors: Naik, Ravi, Won, Misun, Ban, Hyun Seung, Bhattarai, Deepak, Xu, Xuezhen, Eo, Yumi, Hong, Ye Seul, Singh, Sarbjit, Choi, Yongseok, Ahn, Hee-Chul, Lee, Kyeong
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - chemistry
Benzophenones - chemistry
Binding, Competitive
Cell Line, Tumor
Chemistry, Pharmaceutical - methods
Chromatography, Affinity - methods
Drug Design
Drug Discovery
HCT116 Cells
Humans
Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors
Inhibitory Concentration 50
Kinetics
meta-Aminobenzoates - chemistry
Oxygen Consumption
Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors
Recombinant Proteins - chemistry
Structure-Activity Relationship
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Summary: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
1520-4804
DOI:10.1021/jm501241g