Design, synthesis and preliminary bioactivity evaluations of 8-hydroxyquinoline derivatives as matrix metalloproteinase (MMP) inhibitors.


Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: [Email]


Matrix metalloproteinases (MMPs) play important roles in many diseases including cancer. With moderate metal-binding affinity, 8-hydroxyquinoline has gained much interest in current drug design and development. Specially, it has been reported that 8-hydroxyquinoline derivatives serve as MMP-2 inhibitors with micromolar IC50 values. In the current study, a series of 8-hydroxyquinoline derivatives were designed and synthesized as new MMP-2 and MMP-9 inhibitors. The most active compounds 5e and 5h not only displayed good inhibitory activities against MMP-2/9 with IC50 at submicromolar level, but also possessed potent anti-proliferative, anti-invasive and anti-angiogenesis activity in A549 cell line. Western blot also revealed that 5e and 5h down-regulate the expression of MMP-2 and MMP-9 in A549 cell line. Moreover, flow cytometry analysis indicated that compound 5e could promote apoptosis of A549 cells in vitro. Molecular docking analysis also revealed favorable binding modes of 5e in the active sites of MMP-2 and MMP-9.


8-Hydroxyquinoline,Anti-angiogenesis,Anti-migration/invasion,MMP-2/9 inhibitors,

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