TY - JOUR
T1 - N-O-Isopropyl Sulfonamido-Based Hydroxamates as Matrix Metalloproteinase Inhibitors
T2 - Hit Selection and in Vivo Antiangiogenic Activity
AU - Nuti, Elisa
AU - Cantelmo, Anna Rita
AU - Gallo, Cristina
AU - Bruno, Antonino
AU - Bassani, Barbara
AU - Camodeca, Caterina
AU - Tuccinardi, Tiziano
AU - Vera, Laura
AU - Orlandini, Elisabetta
AU - Nencetti, Susanna
AU - Stura, Enrico A.
AU - Martinelli, Adriano
AU - Dive, Vincent
AU - Albini, Adriana
AU - Rossello, Armando
PY - 2015/9/24
Y1 - 2015/9/24
N2 - 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.
AB - 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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U2 - 10.1021/acs.jmedchem.5b00367
DO - 10.1021/acs.jmedchem.5b00367
M3 - Article
C2 - 26263024
AN - SCOPUS:84942346084
VL - 58
SP - 7224
EP - 7240
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 18
ER -