Abstract
Matrix metalloproteinases (MMPs) have been shown to be involved in tumor-induced angiogenesis. In particular, MMP-2, MMP-9, and MMP-14 have been reported to be crucial for tumor angiogenesis and the formation of metastasis, thus becoming attractive targets in cancer therapy. Here, we report our optimization effort to identify novel N-isopropoxy-arylsulfonamide hydroxamates with improved inhibitory activity toward MMP-2, MMP-9, and MMP-14 with respect to the previously discovered compound 1. A new series of hydroxamates was designed, synthesized, and tested for their antiangiogenic activity using in vitro assays with human umbilical vein endothelial cells (HUVECs). A nanomolar MMP-2, MMP-9, and MMP-14 inhibitor was identified, compound 3, able to potently inhibit angiogenesis in vitro and also in vivo in the matrigel sponge assay in mice. Finally, X-ray crystallographic and docking studies were conducted for compound 3 in order to investigate its binding mode to MMP-9 and MMP-14.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inhibitors / chemical synthesis
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Angiogenesis Inhibitors / chemistry*
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Angiogenesis Inhibitors / pharmacology
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Animals
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Apoptosis / drug effects
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Cell Movement / drug effects
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Cell Survival / drug effects
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Crystallography, X-Ray
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Human Umbilical Vein Endothelial Cells / cytology
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Human Umbilical Vein Endothelial Cells / drug effects
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Human Umbilical Vein Endothelial Cells / physiology
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Humans
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Hydroxamic Acids / chemical synthesis
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Hydroxamic Acids / chemistry*
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Hydroxamic Acids / pharmacology
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Matrix Metalloproteinase 14 / chemistry
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Matrix Metalloproteinase 14 / metabolism
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Matrix Metalloproteinase 2 / chemistry
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Matrix Metalloproteinase 2 / metabolism
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Matrix Metalloproteinase 9 / chemistry
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Matrix Metalloproteinase 9 / metabolism
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Matrix Metalloproteinase Inhibitors / chemical synthesis
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Matrix Metalloproteinase Inhibitors / chemistry*
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Matrix Metalloproteinase Inhibitors / pharmacology
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Mice
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Molecular Docking Simulation
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Stereoisomerism
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis
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Sulfonamides / chemistry*
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Sulfonamides / pharmacology
Substances
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Angiogenesis Inhibitors
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Hydroxamic Acids
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Matrix Metalloproteinase Inhibitors
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Sulfonamides
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Matrix Metalloproteinase 2
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Matrix Metalloproteinase 9
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Matrix Metalloproteinase 14