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Molecules 2018, 23(4), 885; https://doi.org/10.3390/molecules23040885

Furan- and Thiophene-2-Carbonyl Amino Acid Derivatives Activate Hypoxia-Inducible Factor via Inhibition of Factor Inhibiting Hypoxia-Inducible Factor-1

1
Center for Education and Research in Agricultural Innovation, Faculty of Agriculture, Saga University, 152-1 Shonan-cho, Karatsu, Saga 847-0021, Japan
2
Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan
3
Department of Molecular Medicine and Therapy, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
4
Keihanshin Consortium for Fostering the Next Generation of Global Leaders in Research (K-CONNEX), Kyoto University, Kyoto 606-8501, Japan
5
Department of Applied Biosciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan
6
Department of Applied Biochemistry and Food Science, Faculty of Agriculture, Saga University, 1 Honjyo-machi, Saga, 840-8502, Japan
*
Author to whom correspondence should be addressed.
Received: 9 March 2018 / Revised: 10 April 2018 / Accepted: 10 April 2018 / Published: 11 April 2018
(This article belongs to the Special Issue Directed Drug Design and Molecular Therapy)
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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. View Full-Text
Keywords: hypoxia inducible factor; factor inhibiting hypoxia inducible factor; furan; thiophene hypoxia inducible factor; factor inhibiting hypoxia inducible factor; furan; thiophene
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Kawaguchi, S.-I.; Gonda, Y.; Yamamoto, T.; Sato, Y.; Shinohara, H.; Kobiki, Y.; Ichimura, A.; Dan, T.; Sonoda, M.; Miyata, T.; Ogawa, A.; Tsujita, T. Furan- and Thiophene-2-Carbonyl Amino Acid Derivatives Activate Hypoxia-Inducible Factor via Inhibition of Factor Inhibiting Hypoxia-Inducible Factor-1. Molecules 2018, 23, 885.

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