Inhibition of Invasion and Capillary-like Tube Formation by Retrohydroxamate-based MMP Inhibitors

Department of Bio-engineering, College of Engineering, Hanyang University, Seoul 133-791, KoreaReceived February 7, 2011, Accepted April 26, 2011Matrix metalloproteinases (MMPs), a family of zinc-containing endopeptidases, participate in many normalprocesses such as embryonic development and wound repair, and in many pathological situations such ascancer, atherosclerosis,and arthritis. Peptidomimetic MMP inhibitors were designed and synthesized with N-formylhydroxylamine (retrohydroxamate) as a zinc-binding group and various side chains on the α, P1', andP2' positions. Using in vitro MMP assays with purified MMPs (MMP-1, MMP-2, MMP-3, MMP-9, and MMP-14) and fluorogenic peptide substrates, it was found that compounds 2d and 2g selectively inhibit gelatinases(MMP-2 and MMP-9) and interstitial collagenase (MMP-1). They also inhibited the chemo-invasion offibrosarcoma HT-1080 cells and tube formation of human umbilical vascular endothelial cells in a dose-dependent manner. Our results suggest that retrohydroxamate-based MMP inhibitors, especially compounds2d and 2g, have the potential to be used as therapeutic drugs for cancer and other MMP-related diseases. Key Words : Inhibitor, Invasion, Matrix metalloproteinase (MMP), N-Formylhydroxylamine, Retrohydrox-amateIntroductionMatrix metalloproteinases (MMPs) are endopeptidasesthat can cleave virtually any component of the extracellularmatrix. Under normal physiological conditions, the activitiesof MMPsare precisely regulated by the level of transcrip-tion, by activationof precursor zymogens, by inhibition ofendogenous inhibitors,and by interaction with specificmatrix components. Deregulation of MMP activity is involv-ed in many disastrous diseases such as tumor invasion,metastasis, atherosclerosis,aneurysms, arthritis, tissue ulcers,and fibrosis.