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 <i>N</i>-isopropoxy-arylsulfonamide hydroxamates with improved
inhibitory activity toward MMP-2, MMP-9, and MMP-14 with respect to
the previously discovered compound <b>1</b>. 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 <b>3</b>, 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 <b>3</b> in order to investigate its binding mode to MMP-9 and MMP-14