Abstract
Induction of a series of anti-hypoxic proteins protects cells during exposure to hypoxic conditions. Hypoxia-inducible factor-α (HIF-α) is a major transcription factor that orchestrates this protective effect. To activate HIF exogenously, without exposing cells to hypoxic conditions, many small-molecule inhibitors targeting prolyl hydroxylase domain-containing protein have been developed. In addition, suppression of factor inhibiting HIF-1 (FIH-1) has also been shown to have the potential to activate HIF-α. However, few small-molecule inhibitors of FIH-1 have been developed. In this study, we synthesized a series of furan- and thiophene-2-carbonyl amino acid derivatives having the potential to inhibit FIH-1. The inhibitory activities of these compounds were evaluated in SK-N-BE(2)c cells by measuring HIF response element (HRE) promoter activity. Several furan- and thiophene-2-carbonyl amino acid derivatives inhibited FIH-1 based on correlations among the docking score of the FIH-1 active site, the chemical structure of the compounds, and biological HIF-α/HRE transcriptional activity.
Highlights
Hypoxia-inducible factors (HIFs) are pivotal transcription factors that contribute to the hypoxic stress response [1,2,3,4,5,6,7,8]
factor inhibiting HIF-1 (FIH-1) has an Fe atom in its active center, and this Fe is held in place by two histidine and aspartic acid residues. 2OG is a required cofactor that mediates FIH-1 activity
Many inhibitors have been reported to act as antagonists of 2OG [15,16,17,39]; the use of furan- and thiophene-2-carbonyl amino acid derivatives as antagonists of 2OG has not been evaluated
Summary
Hypoxia-inducible factors (HIFs) are pivotal transcription factors that contribute to the hypoxic stress response [1,2,3,4,5,6,7,8]. Enzymes that contribute to HIF-α quenching require molecular oxygen, 2-oxoglutarate (2OG), and ferric (Fe) ions. When cells encounter severe hypoxic conditions, HIF-α hydroxylation is inhibited due to low oxygen levels. HIF-α is stabilized and translocated to the nucleus, where it forms a heterodimeric complex with HIF-β. The HIF complex binds to HIF response element (HRE) ([A/G]CGTC) and transactivates genes that facilitate adaptation to hypoxic and/or ischemic stress, such as vascular endothelial growth factor (VEGF), erythropoietin (EPO), and glucose transporter-1 (GLUT-1)
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