N-O-Isopropyl Sulfonamido-Based Hydroxamates as Matrix Metalloproteinase Inhibitors: Hit Selection and in Vivo Antiangiogenic Activity.
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.
Dipartimento di Farmacia, Università di Pisa , via Bonanno 6, 56126 Pisa, Italy.
Elisa
E
Nuti
Science and Technological Park, IRCCS MultiMedica , via Fantoli 16/15, 20138 Milan, Italy.
Anna Rita
AR
Cantelmo
Laboratory of Translational Research, IRCCS Arcispedale Santa Maria Nuova , viale Risorgimento 80, 42121 Reggio Emilia, Italy.
Cristina
C
Gallo
Science and Technological Park, IRCCS MultiMedica , via Fantoli 16/15, 20138 Milan, Italy.
Antonino
A
Bruno
Science and Technological Park, IRCCS MultiMedica , via Fantoli 16/15, 20138 Milan, Italy.
Barbara
B
Bassani
Division of Immunology, Transplants and Infectious Diseases, IRCCS San Raffaele , via Olgettina 60, 20132 Milano, Italy.
Caterina
C
Camodeca
Dipartimento di Farmacia, Università di Pisa , via Bonanno 6, 56126 Pisa, Italy.
Tiziano
T
Tuccinardi
CEA, iBiTec-S, Service d'Ingenierie Moleculaire des Proteines (SIMOPRO), CE-Saclay 91191 Gif sur Yvette Cedex, France.
Laura
L
Vera
Dipartimento di Farmacia, Università di Pisa , via Bonanno 6, 56126 Pisa, Italy.
Elisabetta
E
Orlandini
Dipartimento di Farmacia, Università di Pisa , via Bonanno 6, 56126 Pisa, Italy.
Susanna
S
Nencetti
CEA, iBiTec-S, Service d'Ingenierie Moleculaire des Proteines (SIMOPRO), CE-Saclay 91191 Gif sur Yvette Cedex, France.
Enrico A
EA
Stura
Dipartimento di Farmacia, Università di Pisa , via Bonanno 6, 56126 Pisa, Italy.
Adriano
A
Martinelli
CEA, iBiTec-S, Service d'Ingenierie Moleculaire des Proteines (SIMOPRO), CE-Saclay 91191 Gif sur Yvette Cedex, France.
Vincent
V
Dive
Laboratory of Translational Research, IRCCS Arcispedale Santa Maria Nuova , viale Risorgimento 80, 42121 Reggio Emilia, Italy.
Adriana
A
Albini
Dipartimento di Farmacia, Università di Pisa , via Bonanno 6, 56126 Pisa, Italy.
Armando
A
Rossello
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D053511:Matrix Metalloproteinase 14 / Q000737:chemistry / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D062105:Molecular Docking Simulation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D013449:Sulfonamides; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053511:Matrix Metalloproteinase 14