Design, synthesis, and biological evaluation of 4-phenoxybenzenesulfonyl pyrrolidine derivatives as matrix metalloproteinase inhibitors.

A series of 4-phenoxybenzenesulfonyl pyrrolidine derivatives were designed, synthesized, and evaluated as matrix metalloproteinases (MMPs) inhibitors. All of the synthesized compounds displayed inhibitory activity against MMP-2 and MMP-9. Compounds 4a, 4e, and 4i displayed more potent activity than the other compounds. While the three compounds mildly or moderately inhibited the proliferation of cancer cells, they significantly suppressed the migration and invasion of cancer cells at relatively low concentrations as determined by a wound healing assay and transwell assay. In addition, compound 4e suppressed vascular endothelial cell tube formation and sprouting of microvessels from aortic rings in vitro in a dose-dependent manner. Compound 4e markedly suppressed the pulmonary metastasis of H22 cells in mice. These findings along with molecular docking results suggested that compound 4e might be a promising candidate for further structural optimization to develop MMP inhibitors as potential anticancer agents.