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

• Published in: European journal of medicinal chemistry 2011-07, Vol.46 (7), p.2617-2629
• Main Authors: Nuti, Elisa, Casalini, Francesca, Santamaria, Salvatore, Gabelloni, Pamela, Bendinelli, Sara, Da Pozzo, Eleonora, Costa, Barbara, Marinelli, Luciana, La Pietra, Valeria, Novellino, Ettore, Margarida Bernardo, M., Fridman, Rafael, Da Settimo, Federico, Martini, Claudia, Rossello, Armando
• Format: Article
• Language: English
• Subjects: Anti-glioma agents; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Line, Tumor; Cell Movement - drug effects; Cell Survival - drug effects; Collagen - chemistry; Diffusion Chambers, Culture; Drug Combinations; General aspects; GPI-Linked Proteins - chemistry; GPI-Linked Proteins - metabolism; Humans; Hydroxamic acids; 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; Matrix Metalloproteinase Inhibitors - chemical synthesis; Matrix Metalloproteinase Inhibitors - pharmacology; Matrix Metalloproteinases, Membrane-Associated - chemistry; Matrix Metalloproteinases, Membrane-Associated - metabolism; Medical sciences; MMP-2; MMP-25; MMP-9; Molecular Docking Simulation; Neuroglia - drug effects; Neuroglia - enzymology; Neuroglia - pathology; Pharmacology. Drug treatments; Proteoglycans - chemistry; Sulfonamides - chemical synthesis; Sulfonamides - pharmacology; Thiophenes - chemical synthesis; Thiophenes - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.03.033

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. [Display omitted] ► MMP-2, MMP-9 and MMP-25 have been recognized to be highly expressed in gliomas. ► A series of sulfonamido-based hydroxamates was designed and synthesized. ► Derivative 5a was found to have nanomolar activity toward MMP-2, MMP-9 and MMP-25. ► This compound also proved to have anti-invasive activity on U87MG glioma cell line.