Synthesis and Structure鈥揂ctivity Relationship Study of Chemical Probes as Hypoxia Induced Factor-1伪/Malate Dehydrogenase 2 Inhibitors

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• 作者：Ravi Naik ; Misun Won ; Hyun Seung Ban ; Deepak Bhattarai ; Xuezhen Xu ; Yumi Eo ; Ye Seul Hong ; Sarbjit Singh ; Yongseok Choi ; Hee-Chul Ahn ; Kyeong Lee
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：November 26, 2014
• 年：2014
• 卷：57
• 期：22
• 页码：9522-9538
• 全文大小：599K
• ISSN：1520-4804

文摘

A structure鈥揳ctivity relationship study of hypoxia inducible factor-1伪 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-1伪 (HIF-1伪) 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-1伪 and MDH2. Significantly, the inhibitory effect of the probes on HIF-1伪 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.