title: Development of 3,5-dinitrobenzoate-based 5-lipoxygenase inhibitors.
abstract: Human 5-lipoxygenase (5-LOX) is a well-validated target for anti-inflammatory therapy. Development of novel 5-LOX inhibitors with higher activities is highly demanded. In previous study, we have built a model for the active conformation of human 5-LOX, and identified naphthalen-1-yl 3,5-dinitrobenzoate (JMC-4) as a 5-LOX inhibitor by virtual screening. In the present work, 3,5-dinitrobenzoate-based 5-lipoxygenase inhibitors were developed. Twenty aryl 3,5-dinitrobenzoates, N-aryl 3,5-dinitrobenzamides and analogues were designed and synthesized. Several of them were found with significantly increased activities according to cell-free assay and human whole blood assay. The structure-activity relationship study may provide useful insights for designing effective 5-LOX inhibitors.
authors.affiliation: BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Center for Quantitative Biology, Peking University, Beijing 100871, China.
authors.forename: Erchang
authors.initials: E
authors.lastname: Shang
authors.affiliation: BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Center for Quantitative Biology, Peking University, Beijing 100871, China. Electronic address: liuying@pku.edu.cn.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Center for Quantitative Biology, Peking University, Beijing 100871, China.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Wu
authors.affiliation: BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Center for Quantitative Biology, Peking University, Beijing 100871, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Center for Quantitative Biology, Peking University, Beijing 100871, China.
authors.forename: Chong
authors.initials: C
authors.lastname: He
authors.affiliation: BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Center for Quantitative Biology, Peking University, Beijing 100871, China.
authors.forename: Luhua
authors.initials: L
authors.lastname: Lai
mesh_terms: D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D009579:Nitrobenzoates / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D016859:Lipoxygenase Inhibitors; D009579:Nitrobenzoates; C026017:3,5-dinitrobenzoic acid; D001094:Arachidonate 5-Lipoxygenase
keywords: 3,5-Dinitrobenzoate; 5-Lipoxygenase inhibitors; Cell-free assay; Human whole blood assay; SAR study