Synthesis and biological evaluation in U87MG glioma cells of (ethynylthiophene)sulfonamido-based hydroxamates as matrix metalloproteinase inhibitors

Elisa Nuti; Francesca Casalini; Salvatore Santamaria; Pamela Gabelloni; Sara Bendinelli; Eleonora Da Pozzo; Barbara Costa; Luciana Marinelli; Valeria La Pietra; Ettore Novellino; M Margarida Bernardo; Rafael Fridman; Federico Da Settimo; Claudia Martini; Armando Rossello

doi:10.1016/j.ejmech.2011.03.033

Synthesis and biological evaluation in U87MG glioma cells of (ethynylthiophene)sulfonamido-based hydroxamates as matrix metalloproteinase inhibitors

Eur J Med Chem. 2011 Jul;46(7):2617-29. doi: 10.1016/j.ejmech.2011.03.033. Epub 2011 Apr 2.

Authors

Elisa Nuti¹, Francesca Casalini, Salvatore Santamaria, Pamela Gabelloni, Sara Bendinelli, Eleonora Da Pozzo, Barbara Costa, Luciana Marinelli, Valeria La Pietra, Ettore Novellino, M Margarida Bernardo, Rafael Fridman, Federico Da Settimo, Claudia Martini, Armando Rossello

Affiliation

¹ Dipartimento di Scienze Farmaceutiche, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy.

Abstract

Matrix metalloproteinases (MMPs) are important factors in gliomas since these enzymes facilitate invasion into the surrounding brain and participate in neovascularization. In particular, the gelatinases (MMP-2 and MMP-9), and more recently MMP-25, have been shown to be highly expressed in gliomas and have been associated with disease progression. Thus, inhibition of these MMPs may represent a promising non-cytotoxic approach to glioma treatment. We report herein the synthesis and biological evaluation of a series of 4-butylphenyl(ethynylthiophene)sulfonamido-based hydroxamates. Among the new compounds tested, a promising derivative, 5a, was identified, which exhibits nanomolar inhibition of MMP-2, MMP-9, and MMP-25, but weak inhibitory activity toward other members of the MMP family. This compound also exhibited anti-invasive activity of U87MG glioblastoma cells at nanomolar concentrations, without affecting cell viability.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Cell Movement / drug effects
Cell Survival / drug effects
Collagen / chemistry
Diffusion Chambers, Culture
Drug Combinations
GPI-Linked Proteins / chemistry
GPI-Linked Proteins / metabolism
Humans
Hydroxamic Acids / chemical synthesis*
Hydroxamic Acids / pharmacology
Laminin / chemistry
Matrix Metalloproteinase 2 / chemistry
Matrix Metalloproteinase 2 / metabolism
Matrix Metalloproteinase 9 / chemistry
Matrix Metalloproteinase 9 / metabolism
Matrix Metalloproteinase Inhibitors / chemical synthesis*
Matrix Metalloproteinase Inhibitors / pharmacology
Matrix Metalloproteinases, Membrane-Associated / chemistry
Matrix Metalloproteinases, Membrane-Associated / metabolism
Molecular Docking Simulation
Neuroglia / drug effects*
Neuroglia / enzymology
Neuroglia / pathology
Proteoglycans / chemistry
Sulfonamides / chemical synthesis*
Sulfonamides / pharmacology
Thiophenes / chemical synthesis*
Thiophenes / pharmacology

Substances

Antineoplastic Agents
Drug Combinations
GPI-Linked Proteins
Hydroxamic Acids
Laminin
Matrix Metalloproteinase Inhibitors
Proteoglycans
Sulfonamides
Thiophenes
matrigel
Collagen
Matrix Metalloproteinases, Membrane-Associated
matrix metalloproteinase 25
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9

Abstract

Publication types

MeSH terms

Substances

Grants and funding