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

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.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► 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.