Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 18, Pages 7224-7240Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b00367
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Funding
- Italian Ministry of Education, University and Research (MIUR, PRIN) [20109MXHMR_007]
- University of Pisa (Fondi di Ateneo)
- Italian Association for Cancer Research [AIRC 10228]
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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.
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