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http://dx.doi.org/10.5012/bkcs.2011.32.6.2032

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

Choi, Seung-Su (Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University)
Ji, Ae-Ri (Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University)
Yu, Seung-Woo (Research Laboratories, ILDONG Pharmaceuticals Co., Ltd.)
Cho, Bong-Hwan (Research Laboratories, ILDONG Pharmaceuticals Co., Ltd.)
Park, Jung-Dae (Department of Chemistry, POSTECH)
Park, Jun-Hyoung (Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University)
Lee, Hyun-Soo (Department of Chemistry, Sogang University)
Ryu, Seong-Eon (Department of Bio-engineering, College of Engineering, Hanyang University)
Kim, Dong-Han (Department of Chemistry, POSTECH)
Kang, Jae-Hoon (Research Laboratories, ILDONG Pharmaceuticals Co., Ltd.)
Lee, Seung-Taek (Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University)
Publication Information
Bulletin of the Korean Chemical Society / v.32, no.6, 2011 , pp. 2032-2038 More about this Journal
Abstract
Matrix metalloproteinases (MMPs), a family of zinc-containing endopeptidases, participate in many normal processes such as embryonic development and wound repair, and in many pathological situations such as cancer, 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 ${\alpha}$, P1', and P2' 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 of fibrosarcoma 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 compounds 2d and 2g, have the potential to be used as therapeutic drugs for cancer and other MMP-related diseases.
Keywords
Inhibitor; Invasion; Matrix metalloproteinase (MMP); N-Formylhydroxylamine; Retrohydroxamate;
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