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Research Article

2-Arylbenzo[b]furan derivatives as potent human lipoxygenase inhibitors

Li LangShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China,

Ningning DongShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China,

Deyan WuShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China,

Xue YaoShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China,

Weiqiang LuShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China, and Correspondence[email protected]

Chen ZhangShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China,

Ping OuyangShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China,

Jin ZhuShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China,

Yun TangShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China,

Wei WangShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China, ;Department of Chemistry & Chemical Biology, University of New Mexico, Albuquerque, NM, USA

Jian LiShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China, Correspondence[email protected]

Jin HuangShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China, Correspondence[email protected] [email protected]

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Abstract

Human lipoxygenases (LOXs) have been emerging as effective therapeutic targets for inflammatory diseases. In this study, we found that four natural 2-arylbenzo[b]furan derivatives isolated from Artocarpus heterophyllus exhibited potent inhibitory activities against human LOXs, including moracin C (1), artoindonesianin B-1 (2), moracin D (3), moracin M (4). In our in vitro experiments, compound 1 was identified as the most potent LOX inhibitor and the moderate subtype selective inhibitor of 12-LOX. Compounds 1 and 2 act as competitive inhibitors of LOXs. Moreover, 1 significantly inhibits LTB4 production and chemotactic capacity of neutrophils, and is capable of protecting vascular barrier from plasma leakage in vivo. In addition, the preliminary structure–activity relationship analysis was performed based on the above four naturally occurring (1–4) and six additional synthetic 2-arylbenzo[b]furan derivatives. Taken together, these 2-arylbenzo[b]furan derivatives, as LOXs inhibitors, could represent valuable leads for the future development of therapeutic agents for inflammatory diseases.

Keywords:

Declaration of interest

The authors declare no conflict of interest.

The stable-5-LOX plasmid was from Professor Marcia E. Newcomer (Louisiana State University). pCDNA3–12-LOX and pCDNA3–15-LOX were from by Professor Colin D. Funk (Queen’s University, Canada). Financial support of this research was provided by the National Natural Science Foundation of China [Grants 21222211, 21372001, 91313303, 81402482], the Program for New Century Excellent Talents in University [Grant NCET-12–0853], Shanghai Committee of Science and Technology [Grant 11DZ2260600 and 14ZR1411100], China Postdoctoral Science Foundation grant [2014M551361 and 2015T80415], “Shu Guang” project supported by Shanghai Municipal Education Commission and Shanghai Education Development Foundation [Grant 14SG28], and the Fundamental Research Funds for the Central Universities is gratefully acknowledged.

Supplementary material available online

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2-Arylbenzo[b]furan derivatives as potent human lipoxygenase inhibitors

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2-Arylbenzo[b]furan derivatives as potent human lipoxygenase inhibitors

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